

### Intralipid is a Magic Bullet in Cancer treatment?

### Joseph Eldor, MD

Theoretical Medicine Institute, Jerusalem, Israel

Copyright ©2019 by Joseph Eldor, MD

Smashwords Edition

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### Contents

1. Propofol in Cancer treatment

2. Intralipid in Cancer treatment

3. Mitochondria in Cancer

4. Intralipid in Mitochondria

5. Intralipid and Propofol

Propofol in Cancer treatment

The main purpose of this study was to evaluate propofol and its combined effect with cisplatin on apoptosis of cervical cancer cells and molecular mechanisms of this phenomenon.

The effects of propofol and cisplatin on cell viability and apoptosis were detected by cell counting kit-8.CCK-8) assay, colony formation assay and flow cytometry assay. Besides, protein expression of EGFR/JAK2/STAT3 pathway was determined by western blot. STAT3 was over-expressed in cervical cancer cells by STAT3 cDNA. Expression of EGFR and STAT3 protein of human tissues was evaluated by immunohistochemistry.IHC) assay.

In this study, we found that not only propofol alone could inhibit cervical cancer cells viability but also could increase the inhibitory effect of cisplatin on cervical cancer cells growth. Meanwhile, propofol sensitized cervical cancer cells to cisplatin-induced apoptosis but not affected normal cervical cells. In genetic level, propofol could enhance the anti-tumor effect of cisplatin through EGFR/JAK2/STAT3 pathway. Further studies indicated that overexpression of EGFR and STAT3 is related to poor prognoses in cervical cancer patients, which contributed to confirm the clinical role of combined application of propofol and cisplatin.

Propofol enhances the cisplatin-induced cell apoptosis cervical cancer cells via EGFR/JAK2/STAT3 pathway and may be developed as a potential therapeutic agent to treat cervical cancer.1

Propofol, an intravenous anesthetic agent, has been found to inhibit growth of breast cancer cells. However, the mechanisms underlying the antitumor are not known. A recent report has found that propofol could significantly downregulate miR-24 expression in the human malignant cancers. In breast cancer cells, overexpression of miR-24 promotes cell proliferation and inhibits cell apoptosis by downregulation of p27. The miR-24 has been reported to be overexpressed in breast cancer and breast cancer cell lines. In the present study, we hypothesized that propofol induces apoptosis of breast cancer cells by miR-24/p27 signal pathway.

Breast cancer MDA-MB-435 cells were exposed to propofol.10 μM) for 6 hr and cell death was assessed using TUNEL staining, Flow cytometry and cleaved caspase-3 expression. microRNA-24.miR-24) expression was assessed using quantitative reverse transcription polymerase chain reaction.qRT-PCR miR-24 was overexpressed using a miR-24 mimic. P27 was knocked down using a small interfering RNA. p27 and cleaved caspase-3 expression was assessed by Western blot.

MDA-MB-435 exposed to propofol showed a significant increase in apoptotic cells, followed by the downregulation of miR-24, upregulation of p27 expression and cleaved caspase-3 expression. Targeting p27 inhibits propofol-induced cell apoptosis; miR-24 overexpression decreased propofol-induced cell apoptosis, cleaved caspase-3 and p27 expression.

Propofol induces cell death in MDA-MB-435 cells via inactivation of miR-24/p27 signal pathway.2

Propofol is one of the most extensively used intravenous anesthetic agents and it can influence the biological behavior of gastric cancer. However, the underlying mechanism is poorly understood. In the present study, we found that propofol significantly inhibited cell proliferation, invasion and migration, and also promoted apoptosis in gastric carcinoma cell lines SGC-7901 and MGC-803, as detected using MTT, colony formation and flow cytometry assays, respectively. Moreover, propofol.10 and 20 µM) markedly upregulated the expression of inhibitor of growth 3.ING3), which was lower in SGC-7901 and MGC-803 cells compared with that noted in normal human gastric epithelial cell lines GES-1 and HFE145. Furthermore, we transfected SGC-7901 and MGC-803 cells with ING3 overexpression vectors or ING3 small interference RNA.siING3), respectively, to assess the role of ING3 in propofol-induced antitumor activity. The siING3 transfection reversed the effects of propofol on the biological behavior of gastric cancer cells, while transfection of ING3 promoted the effects of propofol. In conclusion, our results indicate that propofol exerts an inhibitory effect on the growth and survival of gastric cancer cells by interfering with ING3 degradation.3

Propofol.2, 6-diisopropylphenol) is the commonly used intravenous sedative-hypnotic agent. Accumulating evidence shows that propofol affects cancer development by direct and indirect ways. In this review, we will provide an overview of the effects of propofol on cancer development and chemotherapy, with a special focus on the underlying molecular mechanisms involved. Propofol regulates both microRNAs.miRNAs) and long non-coding RNAs.lncRNAs), and serves as a regulator of different signaling pathways including hypoxia-inducible factor-1α.HIF-1α), mitogen-activated protein kinase.MAPK), nuclear factor-kappaB.NF-κB), and nuclear factor E2-related factor-2.Nrf2) pathways. In addition, propofol modulates host immune function. Possible correlation between propofol and cancer should be verified in further studies, including animal trials and prospective clinical studies.4

Propofol is a frequently used intravenous anesthetic agent. Recent studies show that propofol exerts a number of non-anesthetic effects. The present study aimed to investigate the effects of propofol on lung cancer cell lines H1299 and H1792 and functional role of microRNA.miR)-486 in these effects. H1299 and/or H1792 cells were treated with or without propofol and transfected or not with miR-486 inhibitor, and then cell viability and apoptosis were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.MTT) and flow cytometry. The expression of miR-486 was determined by quantitative real-time polymerase chain reaction.qRT-PCR) with or without propofol treatment. Western blot was performed to analyze the protein expression of Forkhead box, class O.FOXO) 1 and 3, Bcl-2 interacting mediator of cell death.Bim), and pro- and activated caspases-3. Results showed that propofol significantly increased the miR-486 levels in both H1299 and H1792 cells compared to untreated cells in a dose-dependent manner.P<0.05 or P<0.01 Propofol statistically decreased cell viability but increased the percentages of apoptotic cells and protein expressions of FOXO1, FOXO3, Bim, and pro- and activated caspases-3; however, miR-486 inhibitor reversed the effects of propofol on cell viability, apoptosis, and protein expression.P<0.05 or P<0.01 In conclusion, propofol might be an ideal anesthetic for lung cancer surgery by effectively inhibiting lung cancer cell viability and inducing cell apoptosis. Modulation of miR-486 might contribute to the anti-tumor activity of propofol.5

Propofol is one of the most commonly used intravenous anesthetic agents during cancer resection surgery. A previous study has found that propofol can inhibit invasion and induce apoptosis of ovarian cancer cells. However, the underlying mechanisms are not known. miR-9 has been reported to be little expressed in ovarian cancer cells, which has been related to a poor prognosis in patients with ovarian cancer. Studies have also demonstrated that propofol could induce microRNAs expression and suppress NF-κB activation in some situations. In the present study, we assessed whether propofol inhibits invasion and induces apoptosis of ovarian cancer cells by miR-9/NF-κB signaling. Ovarian cancer ES-2 cells were transfected with anti-miR-9 or p65 cDNA or p65 siRNA for 24 h, after which the cells were treated with different concentrations of propofol.1, 5, and 10 μg/mL) for 24 h. Cell growth and apoptosis were detected using MTT assay and flow cytometry analysis. Cell migration and invasion were detected using Transwell and Wound-healing assay. Western blot and electrophoretic mobility shift assay were used to detect different protein expression and NF-κB activity. Propofol inhibited cell growth and invasion, and induced cell apoptosis in a dose-dependent manner, which was accompanied by miR-9 activation and NF-κB inactivation. Knockdown of miR-9 abrogated propofol-induced NF-κB activation and MMP-9 expression, reversed propofol-induced cell death and invasion of ES-2 cells. Knockdown of p65 inhibited NF-κB activation rescued the miR-9-induced down-regulation of MMP-9. In addition, overexpression of p65 by p65 cDNA transfection increased propofol-induced NF-κB activation and reversed propofol-induced down-regulation of MMP-9. Propofolupregulates miR-9 expression and inhibits NF-κB activation and its downstream MMP-9 expression, leading to the inhibition of cell growth and invasion of ES-2 cells.6

Antioxidants induce the proliferation of cancers by decreasing the expression of p53. Propofol, one of the most extensively used intravenous anesthetics, provides its antioxidative activity via activation of the nuclear factor E2-related factor-2.Nrf2) pathway, but the mechanisms involved in the effects remain unknown. Thus, we aimed to investigate the function of p53 and Nrf2 in the human breast cancer cell line MDA-MB-231 following treatment with propofol. The cells were treated with propofol.2, 5 and 10 µg/ml) for 1, 4 and 12 h, and MTT assay was used to evaluate cell proliferation, and a wound healing assay was used to evaluate cell migration. Cell apoptosis, caspase-3 activity, and western blot analysis for p53 and Nrf2 protein were also assessed. Finally, PIK-75, a potent Nrf2 inhibitor, was used to confirm the effects of Nrf2 after treatment with propofol. Treatment of MDA-MB 231 cells with propofol resulted in increased proliferation and migration in a dose- and time-dependent manner. After treatment with propofol for 12 h, the Nrf2 protein expression was increased, while the percentage of apoptotic cells, caspase-3 activity, and expression of p53 were significantly decreased. Additionally, treatment with the Nrf2 inhibitor increased the percentage of apoptotic cells, inhibited the migration almost completely, and decreased the degree of proliferation, while the expression of p53 was not affected. In conclusion, propofol increased the proliferation of human breast cancer MDA-MB 231 cells, which was at least partially associated with the inhibition of the expression of p53, and induced cell migration, which was involved in the activation of the Nrf2 pathway.7

Commonly used inhalational hypnotics, such as sevoflurane, are pro-inflammatory, whereas the intravenously administered hypnotic agent propofol is anti-inflammatory and anti-oxidative. A few clinical studies have indicated similar effects in patients. We examined the possible association between patient survival after radical cancer surgery and the use of sevoflurane or propofol anaesthesia.

Demographic, anaesthetic, and surgical data from 2,838 patients registered for surgery for breast, colon, or rectal cancers were included in a database. This was record-linked to regional clinical quality registers. Cumulative 1- and 5-year overall survival rates were assessed using the Kaplan-Meier method, and estimates were compared between patients given propofol.n = 903) or sevoflurane.n = 1,935 In a second step, Cox proportional hazard models were calculated to assess the risk of death adjusted for potential effect modifiers and confounders.

Differences in overall 1- and 5-year survival rates for all three sites combined were 4.7%.p = 0.004) and 5.6%.p < 0.001), respectively, in favour of propofol. The 1-year survival for patients operated for colon cancer was almost 10% higher after propofol anaesthesia. However, after adjustment for several confounders, the observed differences were not statistically significant.

Propofol anaesthesia might be better in surgery for some cancer types, but the retrospective design of this study, with uneven distributions of several confounders, distorted the picture. These uncertainties emphasize the need for a randomized controlled trial.8

Propofol has been widely used in lung cancer resections. Some studies have demonstrated that the effects of propofol might be mediated by microRNAs.miRNAs This study aimed to investigate the effects and mechanisms of propofol on lung cancer cells by regulation of miR-1284. A549 cells were treated with different concentrations of propofol, while transfected with miR-1284 inhibitor, si-FOXM1, and their negative controls. Cell viability, migration, and invasion, and the expression of miR-1284, FOXM1, and epithelial-mesenchymal transition.EMT) factors were detected by CCK-8, Transwell, qRT-PCR, and Western blot assays, respectively. In addition, the regulatory and binding relationships among propofol, miR-1284, and FOXM1 were assessed, respectively. Results showed that propofol suppressed A549 cell viability, migration, and invasion, upregulated E-cadherin, and downregulated N-cadherin, vimentin, and Snail expressions. Moreover, propofol significantly promoted the expression of miR-1284. miR-1284 suppression abolished propofol-induced decreases of cell viability, migration, and invasion, and increased FOXM1 expression and the luciferase activity of FOXM1-wt. Further, miR-1284 negatively regulated FOXM1 expression. FOXM1 knockdown reduced cell viability, migration, and invasion by propofol treatment plus miR-1284 suppression. In conclusion, our study indicated that propofol could inhibit cell viability, migration, invasion, and the EMT process in lung cancer cells by regulation of miR-1284.9

Prostate cancer is the second most frequently diagnosed cancer worldwide. Hypoxia-induced epithelial-mesenchymal transition.EMT), driven by hypoxia-inducible factor 1α.HIF-1α), is involved in cancer progression and metastasis. The present study was designed to explore the role of propofol in hypoxia-induced resistance of prostate cancer cells to docetaxel. We used the Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine incorporation assay to measure cell viability and cell proliferation, respectively, in prostate cancer cell lines. Then, we detected HIF-1α, E-cadherin, and vimentin expression using western blotting. Propofol reversed the hypoxia-induced docetaxel resistance in the prostate cancer cell lines. Propofol not only decreased hypoxia-induced HIF-1α expression, but also reversed hypoxia-induced EMT by suppressing HIF-1α. Furthermore, small interfering RNA-mediated silencing of HIF-1α reversed the hypoxia-induced docetaxel resistance, although there was little change in docetaxel sensitivity between the hypoxia group and propofol group. The induction of hypoxia did not affect E-cadherin and vimentin expression, and under the siRNA knockdown conditions, the effects of propofol were obviated. These data support a role for propofol in regulating EMT in prostate cancer cells. Taken together, our findings demonstrate that propofol plays an important role in hypoxia-induced docetaxel sensitivity and EMT in prostate cancer cells and that it is a potential drug for overcoming drug resistance in prostate cancer cells via HIF-1α suppression.10

This study investigated the effects of propofol on gastric cancer MKN45 cell proliferation, migration, invasion and apoptosis, as well as underlying potential mechanisms.

The viability, proliferation, apoptosis, migration and invasion of MKN45 cells were assessed using CCK-8 assay, BrdU incorporation assay, Annexin V-FITC/PI staining, two-chamber migration.invasion) assay and western blotting, respectively. qRT-PCR was performed to measure the expression of microRNA-195.miR-195 Cell transfection was conducted to down-regulate the expression of miR-195.

Propofol treatment suppressed MKN45 cell proliferation, migration and invasion, but promoted cell apoptosis. The expression of miR-195 was increased after propofol treatment. Suppression of miR-195 reversed the propofol-induced MKN45 cell proliferation, migration and invasion inhibition, as well as apoptosis. Moreover, Propofol treatment inactivated JAK/STAT and NF-κB pathways in MKN45 cells. Suppression of miR-195 reversed the propofol-induced inactivation of JAK/STAT and NF-κB pathways. Inhibition of JAK/STAT and NF-κB pathways reversed the effects of miR-195 suppression on propofol-induced MKN 45 cell proliferation, migration and invasion inhibition, as well as apoptosis enhancement.

Propofol inhibited proliferation, migration and invasion of gastric cancer MKN45 cells by up-regulating miR-195 and then inactivating JAK/STAT and NF-κB pathways. Propofol could be as an effective therapeutic medicine for gastric cancer treatment.11

Propofol is one of the extensively and commonly used intravenous anesthetic agents. The current study aimed to evaluate the effects of propofol on the behavior of human gastric cancer cells and the molecular mechanisms of this activity. The effects of propofol on SGC7901 and AGS cell proliferation, apoptosis, and invasion were detected by MTT assay, flow cytometric analysis, and matrigel invasion assay. Real-time polymerase chain reaction.PCR) was used to assess microRNA.miR)-221 expression. miR-221 mimics were transfected into SGC7901 and AGS cells to assess the role of miR- 221 in propofol-induced anti-tumor activity. Propofol significantly inhibited cell proliferation and invasion and promoted apoptosis of SGC7901 and AGS cells. Propofol also efficiently reduced miR-221 expression. Moreover, transfection of miR-221 mimics reversed the effects of propofol on the biological behavior of gastric cancer cells. Propofol can effectively inhibit proliferation and invasion and induce apoptosis of gastric cancer cells through, at least partly, downregulation of miR-221 expression.12

.

Although significant advances have been made toward understanding the molecular mechanisms underlying the effect of propofol on tumor cell metastasis, less is known regarding how cell membrane and cytoskeletal ultrastructure are affected in this process. Here, we investigated the relationship between cell morphology and cell size, which are features mainly defined by the cytoskeleton.

To confirm the effects of propofol on the migratory ability of human cervical carcinoma cells, cell migration and invasion were examined through scratch wound healing and transwell membrane assays. Furthermore, HeLa cells cultivated with different concentrations of propofol were examined by confocal microscopy and atomic force microscopy.AFM), and the mean optical density and migration ability of these cells were also assessed. In addition, cell membrane morphology was inspected using AFM.

The results of the wound healing and transwell membrane assays indicated that propofol decreases the migratory ability of cervical carcinoma cells compared to control cells. A comparative analysis of the test results revealed that short-term.3 h) exposure to propofol induced marked changes in cell membrane microstructure and in the cytoskeleton in a dose-dependent manner. These morphological changes in the cell membrane were accompanied by cytoskeleton.F-actin) derangement. The present findings demonstrate a close relationship between changes in cell membrane ultrastructure and cytoskeletal alterations.F-actin) in propofol-treated HeLa cells. AFM scanning analysis showed that cell membrane ultrastructure was significantly changed, including a clear reduction in membrane roughness.

The influence of propofol on the HeLa cell cytoskeleton can be directly reflected by changes in cellular morphology, as assessed by AFM. Moreover, the use of AFM is a good method for investigating propofol-mediated changes within cytoskeletal ultrastructure.13

To clarify the effect of anaesthetic agents on cancer immunity, we evaluated the effects of propofol and sevoflurane on natural killer.NK) cell, cytotoxic T lymphocyte.CTL) counts and apoptosis rate in breast cancer and immune cells co-cultures from patients who underwent breast cancer surgery.

Venous blood samples were collected after inducing anaesthesia and at 1 and 24 h postoperatively in patients who had undergone breast cancer surgery. The patients were allocated randomly to the propofol- or sevoflurane-based anaesthesia groups. We counted and detected apoptosis in cancer cell, NK cell and CTL of patients with breast cancer by co-culture with a breast cancer cell line in both groups. We also evaluated changes in the cytokines tumour necrosis factor-alpha, interleukin.IL)-6 and IL-10 during the perioperative period.

Forty-four patients were included in the final analysis. No difference in NK cell count, CTL count or apoptosis rate was detected between the groups. Furthermore, the number of breast cancer cells undergoing apoptosis in the breast cancer cell co-cultures was not different between the groups. No changes in cytokines were detected between the groups.

Although basic science studies have suggested the potential benefits of propofol over a volatile agent during cancer surgery, propofol was not superior to sevoflurane, on the aspects of NK and CTL cells counts with apoptosis rate including breast cancer cell, during anaesthesia for breast cancer surgery in a clinical environment.14

Propofol is an intravenous sedative hypnotic agent of which the growth-inhibitory effect has been reported on various cancers. However, the roles of propofol in endometrial cancer.EC) remain unclear. This study aimed to explore the effects of propofol on EC in vitro and in vivo. Different concentrations of propofol were used to treat Ishikawa cells. Colony number, cell viability, cell cycle, apoptosis, migration, and invasion were analyzed by colony formation, MTT, flow cytometry, and Transwell assays. In addition, the pcDNA3.1-Sox4 and Sox4 siRNA plasmids were transfected into Ishikawa cells to explore the relationship between propofol and Sox4 in EC cell proliferation. Tumor weight in vivo was measured by xenograft tumor model assay. Protein levels of cell cycle-related factors, apoptosis-related factors, matrix metalloproteinases 9.MMP9), matrix metalloproteinases 2.MMP2) and Wnt/β-catenin pathway were examined by western blot. Results showed that propofol significantly decreased colony numbers, inhibited cell viability, migration, and invasion but promoted apoptosis in a dose-dependent manner in Ishikawa cells. Moreover, propofol reduced the expression of Sox4 in a dose-dependent manner. Additionally, propofol significantly suppressed the proportions of Ki67+ cells, but Sox4 overexpression reversed the results. Furthermore, in vivo assay results showed that propofol inhibited tumor growth; however, the inhibitory effect was abolished by Sox4 overexpression. Moreover, propofol inhibited Sox4 expression via inactivation of Wnt/β-catenin signal pathway. Our study demonstrated that propofol inhibited cell proliferation, migration, and invasion but promoted apoptosis by regulation of Sox4 in EC cells. These findings might indicate a novel treatment strategy for EC.15

Perioperative factors are probably essential for different oncological outcomes. This systematic review investigates the literature concerning overall mortality and postoperative complications after cancer surgery with inhalational.INHA) and intravenous anesthesia.TIVA A search was conducted according to the PRISMA guidelines, including studies with patients undergoing surgery for cancer and where TIVA was compared with INHA. Two investigators identified relevant papers in the databases: PubMed, Scopus, EMBASE and the Cochrane Library. Risks of bias assessment tools from the Cochrane Collaboration were used for evaluating quality of evidence. Eight studies with a total of 10,696 patients were included. Four studies reported data regarding overall mortality and four studies reported data regarding postoperative complications. Evidence was evaluated to be of moderate to serious risk of bias. Three retrospective studies presented a hazard ratio.HR) adjusting for several confounders. One study reported an increased overall mortality after INHA with a HR of 1.47.95% CI 1.31-1.64, p≤0.001), while another study reported a tendency of decreased overall mortality after TIVA.HR 0.85, 95% CI 0.72-1.00, p=0.051 A third study showed no difference in the overall mortality, but prolonged recurrence-free survival after TIVA with a HR of 0.48.95% CI 0.27-0.86, p=0.014 In one study, the rate of pulmonary complications was significantly higher after INHA compared with TIVA, while other postoperative complications were comparable. There are currently four propensity-adjusted retrospective studies indicating that TIVA might be the preferred anesthetic choice in cancer surgery. However, evidence is currently of low quality and randomized clinical trials are required for further investigation.16

To investigate the effect of propofol on cell invasion and expressions of aquaporin-3.APQ-3) and matrix metalloproteinase-9.MMP-9) in human lung adenocarcinoma cancer A549 cells.

A549 cells were treated with propofol at the concentrations of 25, 50, and 100 µmol/L for 12 or 24 h. RT-PCR was used to detect the effect of propofol on AQP-3 mRNA level in A549 cells, and the effects of propofol treatments for 24 h on AQP-3 and MMP-9 protein expression and the invasive ability of A549 cells were assessed with Western blotting and Transwell assay, respectively.

Compared with the control cells, the cells treated with 25, 50, and 100 µmol/L propofol showed a obvious inhibition of AQP-3 mRNA expression, with inhibition rates ranging from 0.19 to 0.65 in cells with a 12-h treatment and from 0.13 to 0.41 in cells treated for 24 h; 100 µmol/L propofol treatment for 24 h produced the strongest inhibitory effect.0.13∓0.035, P<0.05 AQP-3 protein expression in cells treated with 25, 50, and 100 µmol/L propofol for 24 h.0.91∓0.009, 0.60∓0.020, and 0.57∓0.006, respectively) and MMP-9 protein expression in cells treated with 50 and 100 µmol/L propofol for 24 h.0.65∓0.006 and 0.46∓0.021, respectively) were significantly lower than those in the control cells.P<0.05 Treatment with 25, 50, and 100 µmol/L propofol for 24 significantly lowered the number of invading cells.122.55∓17.20, 96.33∓5.82, and 74.33∓2.85, respectively) compared with the control group.199.33∓23.88, P<0.05

Treatment with 50 and 100 µmol/L propofol inhibits cell invasion by down-regulating the expression of AQP-3 and MMP-9 in A549 cells.17

Propofol-paravertebral anesthesia.PPA) is a unique combination of paravertebral nerve blocks.PVBs) and propofol that regulates the cellular microenvironment during surgical period. Growing evidence points to its ability to attenuate perioperative immunosuppression of cancers. Abundant studies show that cancer patients who undergo perioperative PPA exhibit less recurrence as well as metastasis. Breast cancer remains a leading cause of cancer-induced death in women. Over the last decades, increasing concerns have been put on the promotional role of PPA in the prognosis of breast cancer patients. Among them, PPA participates in several bioprocesses in the development of breast cancer, including inhibiting hypoxia-inducible factor.HIF) activity, elevating serum concentration of nitric oxide index.NOx), depression of the neuroepithelial cell transforming gene 1.NET1) signal pathway, blocking the nuclear factor kappa B.NF-κB) pathway following an decreased expression of matrix metalloproteinase.MMP), increasing NK cytotoxicity, and affecting transforming growth factor.TGF)-β-targeted ras and HER2/neu gene pathways. In this review, we discuss the effect of PPA on breast cancer metastasis and progression. This will provide an alteration pattern of surgical anesthesia technique in breast cancer patients with poor prognosis.18

We investigated the effect of propofol on activities and tumor-killing ability of natural killer.NK) cells in patients with colon cancer.

Twenty colon cancer patients and 20 healthy subjects were included. Peripheral blood.5 ml) was collected from all patients and healthy subjects. NK cells in peripheral blood were separated by negative screening using immunomagnetic beads. Flow cytometry was used to determine expression of activated receptors, inhibitory receptors, killing effector molecules, and proliferation-associated markers on NK cell surfaces. After in vitro treatment with propofol for 24 h, expression of activated receptors, inhibitory receptors, killing effector molecules, and proliferation-associated markers on NK cell surfaces was examined again. In addition, the tumor-killing effect of NK cells was studied by co-culture with K562 cells or colon cancer SW620 cells at a ratio of 1: 1.

The number of NK cells in peripheral blood from colon cancer patients was increased compared with healthy subjects, but activities and proliferation ability of the NK cells were decreased. The tumor-killing effect of NK cells isolated from colon cancer patients was decreased. Of note, propofol promoted activation of NK cells from colon cancer patients. In addition, propofol increased expression of tumor-killing effector molecules by NK cells and the proliferation ability of NK cells. Propofol also enhanced the killing effect of NK cells on colon cancer cells.

The present study demonstrates that propofol promotes the activity and tumor-killing ability of NK cells in peripheral blood of patients with colon cancer.19

Despite the growing number of cancer cases and cancer surgeries around the world, the pharmacokinetics.PK) and pharmacodynamics.PD) of anesthetics used in this population are poorly understood. Patients operated due to cancer are usually in severe state and often require chemotherapy. It might affect the PK/PD of drugs used in this population. Therefore, in this study we explored the PK/PD of propofol in cancer patients having a major lung surgery. 23 patients that underwent a propofol-fentanyl total intravenous anesthesia were included in the analysis. A large set of demographic, biochemical and hemodynamic parameters was collected for the purpose of covariate analysis. Nonlinear mixed effect modeling in NONMEM was used to analyze the collected data. A three-compartment model was sufficient to describe PK of propofol. The anesthetic effect.AAI index) was linked to the propofol effect site concentrations through a sigmoidal E max model. A slightly higher value of clearance, a lower value of distribution clearance, and a decreased volume of peripheral compartment were observed in our patients, as compared with the literature values reported for healthy volunteers by Schnider et al. and by Eleveld et al. Despite these differences, both models led to a clinically insignificant bias of -8 and -1 % in concentration predictions, as reflected by the median performance error. The C e50 and propofol biophase concentration at the time of postoperative orientation were low and equaled 1.40 and 1.13 mg/L. The population PK/PD model was proposed for cancer patients undergoing a major lung surgery. The large body of studied covariates did not affect PK/PD of propofol significantly. The modification of propofol dosage in the group of patients under study is not necessary when TCI-guided administration of propofol by means of the Schnider model is used.20

Cervical cancer is one of the most common gynecologic malignant tumors. Propofol has been proposed to play a role of antitumor in various cancers. However, the functions and mechanisms of Propofol in cervical cancer is still not clear.

In vitro, the different concentrations of propofol were co-incubated with cervical cancer cell lines, including Hela, Caski and C-33A cells respectively. The pcDNA-HOTAIR plasmid was transfected into cells after the treatment of 10 μg/ml propofol. The cell viability and apoptosis were detected by MTT assay and TUNEL method. In vivo, propofol was injected into mice of transplantation tumor with Caski cells or with pcDNA-HOTAIR treated Caski cells.

Propofol significantly decreased the cell viability and increased the cell apoptosis in Hela, Caski and C-33A cells, while HOTAIR overexpression promoted cell viability and inhibits cell apoptosis. mTOR/p70S6K protein expression levels were also markedly reduced by propofol but the effects were reversed with pcDNA-HOTAIR. In vivo, propofol inhibited the tumor size but had no inhibition effect in HOTAIR overexpression group.

Propofol inhibited tumor size, cell viability and promoted cell apoptosis via inhibiting mTOR/p70S6K pathway mediated by HOTAIR in cervical cancer.21

Anesthetics are documented to affect tumors; therefore, we studied the antiglioma effect of propofol on proliferation and invasiveness of glioma cells and explored the underlying mechanism. C6 glioma cells were cultured and treated with propofol, and cell viability, invasiveness, and migration were measured. Glutamate release was measured using an enzyme-catalyzed kinetic reaction. xCT protein and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid.AMPA) receptor GluR2 subunit protein expression was assessed with Western blot analysis and immunofluorescent staining. We observed that propofol significantly inhibited C6 glioma cell viability, invasiveness, and migration and decreased glutamate release. An agonist of the cystine/glutamate antiporter system.system xc-), N-acetylcysteine.NAC), reversed propofol's effects, and propofol could inhibit C6 glioma cell proliferation by adding excess exogenous glutamate.100μM Finally, propofol increased the surface expression of GluR2, but decreased surface expression of xCT. The effects of propofol on surface expression of GluR2 and xCT could be rescued by.R, S)-AMPA, an agonist of Ca2+ permeable AMPA receptor.CPAR Thus, propofol can inhibit cell viability, invasiveness, and migration of C6 glioma cells, and the CPAR-system xc- pathway contributes to these events.22

Propofol is a commonly used intravenous anesthetic. We evaluated its effects on the behavior of human pancreatic cancer cells and the underlying molecular mechanisms. The effects of propofol on Panc-1 cell proliferation, apoptosis, and invasion were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.MTT) assay, caspase-3 activity measurement, and Matrigel invasion assay. Quantitative polymerase chain reaction.qPCR) was used to assess microRNA-133a.miR-133a) expression. Anti-miR-133a was transfected into Panc-1 cells to assess the role of miR-133a in propofol-induced antitumor activity. Propofol significantly inhibited Panc-1 cell proliferation and invasion, and promoted apoptosis. Propofol also efficiently elevated miR-133a expression. Moreover, transfection of anti-miR-133a reversed the effects of propofol on the biological behavior of Panc-1 cells. Propofol can effectively inhibit proliferation and invasion, and induce apoptosis of pancreatic cancer cells, at least partly through the upregulation of miR-133a expression.23

The anti-cancer activities of intravenous anesthetic drug propofol have been demonstrated in various types of cancers but not in chronic myeloid leukemia.CML

We systematically examined the effect of propofol and its combination with BCR-ABL tyrosine kinase inhibitors.TKIs) in CML cell lines, patient progenitor cells and mouse xenograft model. We analyzed propofol's underlying mechanism focusing on survival pathway in CML cells.

We show that propofol alone is active in inhibiting proliferation and inducing apoptosis in KBM-7, KU812 and K562 cells, and acts synergistically with imatinib or dasatinib, in in vitro cell culture system and in vivo xenograft model. In addition, propofol is more effective in inducing apoptosis and inhibiting colony formation in CML CD34 progenitor cells than normal bone marrow.NBM) counterparts. Combination of propofol and dasatinib significantly eliminates CML CD34 without affecting NBM CD34 cells. We further demonstrate that propofol suppresses phosphorylation of Akt, mTOR, S6 and 4EBP1 in K562. Overexpression of constitutively active Akt significantly reverses the inhibitory effects of propofol in K562, confirm that propofol acts on CML cells via inhibition of Akt/mTOR. Interestingly, the levels of p-Akt, p-mTOR and p-S6 are lower in cells treated with combination of propofol and imatinib than cells treated with propofol or imatinib alone, suggesting that propofol augments BCR-ABL TKI's inhibitory effect via suppressing Akt/mTOR pathway.

Our work shows that propofol can be repurposed to for CML treatment. Our findings highlight the therapeutic value of Akt/mTOR in overcoming resistance to BCR-ABL TKI treatment in CML.24

Propofol is an extensively used intravenous anesthetic agent. The aim of the present study was to evaluate the effects of propofol on the behavior of human gastric cancer cells and the molecular mechanisms associated with this activity. The effects of propofol on proliferation and apoptosis in the SGC-7901 gastric cancer cell line were detected by an MTT assay and measurement of caspase-3 activity. The protein expression levels of matrix metalloproteinase-2.MMP-2) were detected by western blotting. Reverse transcription-quantitative polymerase chain reaction was conducted to evaluate the effect of propofol treatment on microRNA.miR)-451 expression levels and an miR-451 precursor was used to evaluate whether miR-451 overexpression affects MMP-2 expression levels. In addition, the effect of miR-451 on propofol-induced antitumor activity was evaluated using anti-miR-451. Propofol significantly elevated miR-451 expression levels, inhibited SGC-7901 cell proliferation, and promoted apoptosis. Propofol also efficiently reduced MMP-2 protein expression levels. Furthermore, miR-451 overexpression reduced MMP-2 protein expression levels. In addition, neutralization of miR-451 by anti-miR-451 antibody reversed the effect of propofol on cell proliferation and apoptosis and upregulated MMP-2 expression in the SGC-7901 cells. Propofol effectively inhibited proliferation and induced apoptosis in gastric cancer cells, which was partly owing to the downregulation of MMP-2 expression by miR-451.25

Studies on the effects of propofol on the growth of hepatoma xenografts in Balb/c mice.

In an effort to establish a hepatoma-xenograft model of BALB/C mice, human hepatocellular carcinoma cells SMMC-7721 were inoculated subcutaneously into BALB/C mice. Forty mice were randomly divided into five different groups.n=8): control group.C group), Intralipid group.Y group), low dose.50mg/kg) propofol group.P1 group), medium dose.100mg/kg) propofol group.P2 group) and high dose.150mg/kg) propofol group.P3 group The tumor volume was measured before treatment and every 3days after treatment.T0d-T18d, T0represents time point before treatment, T3d-T18d represent time points every 3 days after treatment for a total of 18 days All mice were sacrificed 19 days after drug withdrawal. The tumor masses were extracted, weighed, and the tumor inhibition rate of propofol was calculated. The protein levels of matrix metalloproteinase-2.MMP-2) and vascular endothelial growth factor.VEGF) in the xenografted tumors were analyzed by immunohistochemistry staining.

No statistical significance in the tumor volume at T0d.before treatment), T3d.3 days after treatment), and T6d.6 days after treatment) among the five groups.P>0.05) could be determined. Compared to group C, the tumor volumes in the P1, P2, and P3 groups were found to be significantly decreased in size upon increasing the propofol dosages.P<0.05 There was no statistical significance at time points T9d-T18d in group Y compared to group C.P>0.05 The tumor weights in the P1, P2, and P3 groups were found to be significantly lower as the propofol dosages increased.P<0.05), with no statistical significance determined in group Y.P>0.05 MMP-2 and VEGF protein levels were found to be significantly lower in the P1, P2, and P3 groups as the propofol dosages increased.P<0.05), with no statistical significance in group Y.P>0.05

Within a certain range, propofol was found to inhibit tumor growth and expression of MMP-2 and VEGF proteins in hepatoma xenografts in BALB/C mice in a dose-dependent manner.26

Propofol, a commonly used intravenous anesthetic during cancer resection surgery, has been found to exhibit tumor inhibitory effects in vitro and in vivo. The role of propofol in lung cancer has been previously reported, whereas its action mechanism remains unclear. This study further investigated the effects of propofol on lung cancer A549 cell growth, migration and invasion, as well as the underlying mechanisms.

Cell viability, proliferation, migration, invasion and apoptosis were assessed by CCK-8 assay, BrdU assay, two chamber transwell assay and flow cytometry, respectively. The regulatory effect of propofol on microRNA-372.miR-372) expression in A549 cells was analyzed by qRT-PCR. Cell transfection was used to change the expression of miR-372. The protein expression of key factors involving in cell proliferation, apoptosis, migration and invasion, as well as Wnt/β-catenin and mTOR pathways were analyzed by western blotting.

Propofol inhibited lung cancer A549 cell viability, proliferation, migration, and invasion, but promoted cell apoptosis. Moreover, miR-372 was down-regulated in propofol-treated A549 cells. Overexpression of miR-372 abrogated the effects of propofol on proliferation, migration, invasion and apoptosis of A549 cells. Knockdown of miR-372 had opposite effects. Furthermore, propofol suppressed Wnt/β-catenin and mTOR signaling pathways by down-regulating miR-372.

Propofol inhibits growth, migration and invasion of lung cancer A549 cells at least in part by down-regulating miR-372 and then inactivating Wnt/β-catenin and mTOR pathways.27

To explore the effect of propofol on H19 expression, migration and invasion of human breast cancer MDA-MB-231 cells in vitro.

MDA-MB-231 cells were randomly divided into 5 groups for treatment with basal medium, DMSO, or propofol at concentrations of 25, 50, and 100 µmol/L. H19 expression of the treated cells was assessed with RT-PCR, and the changes of cell motility, migration and invasion were evaluated with wound-healing assay and Transwell assays.

Treatment of the cells with 25, 50, and 100 µmol/L propofol for 24 h down-regulated H19 by 17.83%, 37.50% and 63.67%.P<0.05), and suppressed cell motility by 13.46%, 36.54% and 46.17%.P<0.05), cell migration by 27.93%, 57.90% and 76.51%.P<0.05), and cell invasion by 25.72%, 53.32% and 81.43%.P<0.05), respectively.

Propofol-induced cell migration and invasion suppression are partially mediated by down-regulating H19 in MDA-MB-231 cells in vitro.28

Propofol is one of the most commonly used intravenous anaesthetic agents during cancer resection surgery. It has recently found that propofol has the effect to inhibit cancer cell migration and invasion and sensitize cancer cells to chemotherapy. However, the role of the propofol on the ovarian cancer cells is unknown. In the present study, we explored the effect of propofol on invasion and chemosensitization of ovarian cancer cells to paclitaxel.

The paclitaxel sensitivity of ovarian cancer cell lines HO-8910PM, H0-8910, SKOV-3, OVCAR-3, COC1 and ES-2 were determined by MTT assays. The Slug levels in the cell lines and the effects of propofol on Slug levels in the cell lines were determined by western blot assays. The effect of propofol on invasion, migration and paclitaxel-induced ovarian cancer apoptosis was determined by Boyden chamber assays, cell MTT, TUNEL assays.

The results showed that the cell lines COC1, H0-8910 and ES-2 were sensitive, whereas HO-8910PM, OVCAR-3, SKOV-3, were resistant to paclitaxel. Significant correlation was observed between basal Slug levels and paclitaxel sensitivity. Paclitaxel treatment increased Slug levels. Treatment with propofol induced apoptosis and increased paclitaxel killing of all paclitaxel-sensitive and -resistant ovarian cancer cells followed by significant decrease in the Slug levels. Treatment with propofol inhibits invasion and migration.

These data suggest a new mechanism by which the propofol inhibits invasion and metastasis,enhances paclitaxel-induced ovarian cancer cell apoptosis through suppression of Slug.29

Propofol is one of the most commonly used intravenous anesthetic agents during cancer resection surgery. It can influence proliferation, motility, and invasiveness of cancer cells in vitro and in vivo. However, the role of the propofol in the lung cancer cells remains unclear. In this study, we demonstrated the effects of propofol on the proliferation and the apoptosis of lung cancer cell H460 by using colony formation assay and flow cytometry. Propofol also decreased tumor size and weight in established xenografted tumors. Furthermore, propofol-induced endoplasmic reticulum.ER) stress was determined by Western blot.30

Propofol is a popular anesthetic agent, with potent anti-tumor activity against many cancers. The objective of this study was to explore the potential effect of propofol on papillary thyroid cancer.PTC) in vitro.

Human PTC cell lines TPC-1 and IHH-4 were treated by propofol. ANRIL expression vector.pc-ANRIL) was transfected into TPC-1 cells to overexpress the expression of ANRIL. CCK-8, BrdU assay, transwell assay, flow cytometry and Western blot were performed to evaluate cell proliferation, migration and apoptosis. The expression changes of ANRIL were detected by RT-qPCR.

Propofol with a concentration of 6 μg/mL significantly reduced TPC-1 and IHH-4 cells proliferation and migration, and significantly induced apoptosis. However, 6 μg/mL of propofol had no significant impacts on the proliferation and apoptosis of normal human thyroid follicular epithelial Nthy-ori 3-1 cells. Meanwhile, the expression of ANRIL in TPC-1 cells was down-regulated by propofol. The anti-tumor activity of propofol was attenuated when ANRIL was overexpressed. Additionally, propofol blocked Wnt/β-catenin and NF-κB pathways in an ANRIL-dependent fashion.

Our findings suggested the in vitro anti-tumor potential of propofol in PTC. One possible mechanism involved in the anti-tumor activity was preliminary revealed: propofol down-regulated the expression of ANRIL, and thus blocking Wnt/β-catenin and NF-κB pathways.

The aim of this study is to compare the effects of propofol and sevoflurane anesthesia on perioperative immune response in patients undergoing laparoscopic radical hysterectomy for cervical cancer.Sixty patients with cervical cancer scheduled for elective laparoscopic radical hysterectomy under general anesthesia were randomized into 2 groups. TIVA group received propofol induction and maintenance and SEVO group received sevoflurane induction and maintenance. Blood samples were collected at 30 min before induction.T0); the end of the operation.T1); and 24 h.T2), 48 h.T3), and 72 h.T4) after operation. The T lymphocyte subsets.including CD3+ cells, CD4+ cells, and CD8+ cells) and CD4+/CD8+ ratio, natural killer.NK) cells, and B lymphocytes were analyzed by flow cytometry.After surgery, all immunological indicators except CD8+ cells were significantly decreased in both groups compared to basal levels in T0, and the counts of CD3+ cells, CD4+ cells, NK cells, and the CD4+/CD8+ ratios were significantly lower in the SEVO groups than that in the TIVA group. However, the numbers of B cells were comparable at all the time points between 2 groups.Laparoscopic radical hysterectomy for cervical cancer is associated with postoperative lymphopenia. In terms of protecting circulating lymphocytes, propofol is superior to sevoflurane.

The general anesthetic, propofol, affects chemotherapeutic activity, however, the mechanism underlying its effects remains to be fully elucidated. Our previous study showed that tramadol and flurbiprofen depressed the cytotoxicity of cisplatin via the inhibition of gap junction.GJ) intercellular communication.GJIC) in connexin.Cx)32 HeLa cells. The present study investigated whether the effects of propofol on the cytotoxicity of cisplatin were mediated by GJ in U87 glioma cells and Cx26 transfected HeLa cells. Standard colony formation assay was used to determine the cytotoxicity of cisplatin. Parachute dye coupling assay was used to measure GJ function, and western blot analysis was used to determine the expression levels of Cx32. The results revealed that exposure of the U87 glioma cells and the Cx26-transfected HeLa cells to cisplatin for 1 h reduced clonogenic survival in low density cultures.without GJs) and high density cultures.with GJs However, the toxic effect was higher in the high density culture. In addition, pretreatment of the cells with propofol significantly reduced cisplatin induced cytotoxicity, but only in the presence of functional GJs. Furthermore, propofol significantly inhibited dye coupling through junctional channels, and a long duration of exposure of the cells to propofol downregulated the expression levels of Cx43 and Cx26. These results demonstrated that the inhibition of GJIC by propofol affected the therapeutic efficacy of chemotherapeutic drugs. The present study provides evidence of a novel mechanism underlying the effects of analgesics in counteracting chemotherapeutic efficiency.

Surgery is considered to be the first line treatment for solid tumours. Recently, retrospective studies reported that general anaesthesia was associated with worse long-term cancer-free survival when compared with regional anaesthesia. This has important clinical implications; however, the mechanisms underlying those observations remain unclear. We aim to investigate the effect of anaesthetics isoflurane and propofol on prostate cancer malignancy.

Prostate cancer.PC3) cell line was exposed to commonly used anaesthetic isoflurane and propofol. Malignant potential was assessed through evaluation of expression level of hypoxia-inducible factor-1α.HIF-1α) and its downstream effectors, cell proliferation and migration as well as development of chemoresistance.

We demonstrated that isoflurane, at a clinically relevant concentration induced upregulation of HIF-1α and its downstream effectors in PC3 cell line. Consequently, cancer cell characteristics associated with malignancy were enhanced, with an increase of proliferation and migration, as well as development of chemoresistance. Inhibition of HIF-1α neosynthesis through upper pathway blocking by a PI-3K-Akt inhibitor or HIF-1α siRNA abolished isoflurane-induced effects. In contrast, the intravenous anaesthetic propofol inhibited HIF-1α activation induced by hypoxia or CoCl2. Propofol also prevented isoflurane-induced HIF-1α activation, and partially reduced cancer cell malignant activities.

Our findings suggest that modulation of HIF-1α activity by anaesthetics may affect cancer recurrence following surgery. If our data were to be extrapolated to the clinical setting, isoflurane but not propofol should be avoided for use in cancer surgery. Further work involving in vivo models and clinical trials is urgently needed to determine the optimal anaesthetic regimen for cancer patients.

Propofol is one of the extensively and commonly used intravenous anaesthetic agents. The aims of the current study were to evaluate effects of propofol on the behavior of human epithelial ovarian cancer.EOC) cells and role of miR-let-7i in these effects.

The effects of propofol on cell proliferation and apoptosis were detected by MTT assays and flow cytometry. Real-time polymerase chain reaction.PCR) was used to assess miR-let-7i expression in human EOC cells OVCAR-3 with or without propofol treatment. Finally, the authors evaluated the effect ofmiR-let-7i on propofol-induced anti-tumor activity using anti-miR-let-7i.

Propofol inhibited the proliferation of OVCAR-3 cells in a dose- and time-dependent manner. After exposure to propofol for 24 hours, OVCAR-3 cells showed increased apoptosis and increased expression of miR-let-7i. Finally, anti-miR-let-7i reversed the effect of propofol on cell proliferation and apoptosis.

Propofol can effectively inhibit proliferation and induce apoptosis of EOC cells and modulation of miR-let-7i possibly contributes to the anti-tumor action of propofol.

This study aimed to explore the efficacy of propofol to treat malignant pheochromocytoma.PCC) in vitro and in vivo. In vitro, PC12 cells were treated with different concentrations of propofol.0, 1, 5, and 10 μg/mL) for specific times followed by a MTT assay to detect cell proliferation. Transwell assays were performed to assess the function of propofol on the migration and invasion of PC12 cells, and flow cytometry to analyze cell apoptosis and cell cycle progression. Quantitative real-time polymerase chain reaction was carried out to analyze the expression level of mRNA.Bcl-2, Bax, and CyclinE The levels of Bcl-2, Bax, CyclinE, FOXO1, FOXO3, Bim, procaspase-3, and active caspase-3 were determined by western blotting. In vivo, the effects of propofol on PCC tumor growth were detected by transplanted mouse model. Transferase dUTP nick-end labeling was performed to detect tissue cell apoptosis. The results indicated that propofol inhibited PC12 cell proliferation, prevented cell migration and invasion, and induced the apoptosis of PC12 cells in a dose- and time-dependent manner. Propofol treatment increased the expression of Bax and decreased that of Bcl-2. In addition, propofol significantly induced the G1/S phase arrest in PC12 cells, and the expression of Cyclin E was reduced. Moreover, the levels of FOXO1, FOXO3, Bim, procaspase-3, and active caspase-3 were enhanced by propofol treatment. In vivo, propofol treatment significantly reduced the PCC tumor growth and induced tissue cell apoptosis. In conclusion, propofol has potent anti-PCC activity in vitro and in vivo, and is a potential small-molecule drug for treating malignant PCC.

Propofol possess anticancer properties in several cancers. In the present study, we investigate the effect of propofol on the human esophageal squamous cell carcinomas.ESCC) EC-1 cells in vitro and its molecular mechanisms of action.

EC-1 cells were explored to 10-100 μmol/L propofol for 72 h or 100 μmol/L/mL propofol for 24-72 h. EC-1 cells were explored to 100 μmol/L propofol for 24 h, then was transiently transfected into PcDNA3.1-S100A4 cDNA or PcDNA3.1 plasmid for 48 hrs. MTT, TUNEL, ELISA, migration, tube formation and immunoblotting were analized.

Propofol inhibits invasion, angiogenesis, proliferation and induces apoptosis in a dose and time-dependence manner, followed by deseased S100A4 expression by Western blot assay. Pre-transfection of PcDNA3.1-S100A4 cDNA inhibits propofol-induced apoptosis and promotes invasion and angiogenesis in EC-1 cells in vitro.

Propofol inhibited invasion, angiogenesis and induces apoptosis of human EC-1 cells in vitro through regulation of S100A4 expression. It not only can be an anesthesia agent, but also plays a important role of inhibiting the migration and angiogenesis of ESCC cells in the therapy of ESCC patients.

We previously confirmed that propofol directly inhibited the viability, proliferation, and invasiveness of hepatocellular carcinoma cells in vitro. In this study, we investigated the mechanism underlying the anti-HCC effects of propofol.

In vivo antitumor activity was investigated in tumor-bearing mice following an intraperitoneal injection of propofol, with or without clodrolip. The co-culture system was used to verify that miR-142-3p was transported from macrophages to HCC cells. A miR-142-3p inhibitor was used to down-regulate the expression of miR-142-3p.

Propofol drastically inhibited tumor growth in tomor-bearing mice through macrophage activation, and stimulated tumor-associated macrophages.TAMs) to secrete microvesicles.MVs), which delivered miR-142-3p to HCC cells, resulting in the inhibition of HCC cell invasion. In addition, MVs collected from the plasma of the tumor-bearing mice injected with propofol suppressed tumor growth. More importantly, down-regulation of the expression miR-142-3p reversed the effect of propofol on HCC cell migration.

This study reveals a novel role for propofol in the inhibition of HCC through MV-mediated transfer of miR-142-3p from macrophages to cancer cells in vivo.

This study was implemented to evaluate the effect of genistein and propofol on intracranial tumour model.

Male Fischer 344 rats were subjected to intracranial implantation of 9L gliosarcoma cells. Genistein.100 or 200 mg/kg b.wt) was administered orally regularly from 3rd day after implantation to 25th day. Propofol.20 mg/kg; i.p.) was administered once every 5 days till 25th day and was administered 2 h after genistein.

Human gliosarcoma cells.U251) exposed to genistein.12.5-200 μg) for 24 h exhibited reduced cell viability as assessed by MTT assay and Hoechst staining. In intracranial tumour model, genistein treatment either with or without administration of propofol significantly reduced tumour volume and extended survival time of tumour-bearing rats. Genistein, either alone or with propofol upregulated pro-apoptotic proteins.Bad and Bax) and miRNA-218 expression and also had induced activation of cleaved caspase-3. Activated NF-κB signalling and overproduction of pro-inflammatory cytokines.TNF-α, IL-1β and IL-6) were reduced.

Genistein and propofol effectively inhibited growth of gliosarcoma cells and induced apoptosis. Genistein administration with propofol was found to be more effective than propofol or genistein alone suggesting the positive effects of genistein on propofol-mediated antitumour effects and vice versa.

Epidemiological evidence strongly links fish oil, which is rich in docosahexaenoic acid.DHA) and eicosapentaenoic acid.EPA), with low incidences of several types of cancer. The inhibitory effects of omega-3 polyunsaturated fatty acids on cancer development and progression are supported by studies with cultured cells and animal models. Propofol.2,6-diisopropylphenol) is the most extensively used general anesthetic-sedative agent employed today and is nontoxic to humans at high levels.50 microg/ml Clinically relevant concentrations of propofol.3 to 8 microg/ml; 20 to 50 microM) have also been reported to have anticancer activities. The present study describes the synthesis, purification, characterization and evaluation of two novel anticancer conjugates, propofol-docosahexaenoate.propofol-DHA) and propofol-eicosapentaenoate.propofol-EPA

The conjugates linking an omega-3 fatty acid, either DHA or EPA, with propofol were synthesized and tested for their effects on migration, adhesion and apoptosis on MDA-MB-231 breast cancer cells.

At low concentrations.25 microM), DHA, EPA or propofol alone or in combination had minimal effect on cell adhesion to vitronectin, cell migration against serum and the induction of apoptosis.only 5 to 15% of the cells became apoptotic In contrast, the propofol-DHA or propofol-EPA conjugates significantly inhibited cell adhesion.15 to 30%) and migration.about 50%) and induced apoptosis.about 40%) in breast cancer cells.

These results suggest that the novel propofol-DHA and propofol-EPA conjugates reported here may be useful for the treatment of breast cancer.

Propofol is one of the most commonly used intravenous anaesthetic agents during cancer resection surgery, but the effect of propofol on gallbladder cancer is not clear. NF-E2-related factor 2.Nrf2) is abundantly expressed in cancer cells and relates to proliferation, invasion, and chemoresistance. The aims of the current study were to evaluate effects of propofol on the behavior of human GC cells and role of Nrf2 in these effects.

The effects of propofol on cell proliferation, apoptosis, and invasion were detected by MTT assays, flow cytometry, and transwell assay. Also, activation of Nrf2 was determined by western blot, RT-PCR, and immunofluorescence assays. Nrf2 was knocked-down in GBC-SD cells by shRNA before evaluating the role of Nrf2 in the influence of propofol on biological behaviors.

Propofol promoted the proliferation of GBC-SD cells in a dose- and time- dependent manner. After exposure to propofol for 48 h, GBC-SD cells showed decreased apoptosis and increased invasion. Also, propofol over-expressed Nrf2 at both the protein and mRNA levels and induced translocation of Nrf2 into the nucleus. Finally, loss of Nrf2 by shRNA reversed the effect of propofol on cell proliferation, apoptosis, and invasion.

Propofol induces proliferation and promotes invasion of GC cells through activation of Nrf2.

Tumour cell proliferation, invasion and apoptosis are crucial steps in tumour metastasis. We evaluated the effect of serum from patients undergoing colon cancer surgery receiving thoracic epidural and propofol anaesthesia on colon cancer cell biology. Patients were randomly assigned to receive propofol anaesthesia with a concomitant thoracic epidural.PEA, n = 20) or sevoflurane anaesthesia with opioid analgesia.SGA, n = 20 Venous blood was obtained before induction of anaesthesia and 24 hours postoperatively. The LoVo colon cancer cells were cultured with patient serum from both groups and the effects on proliferation, invasion and apoptosis were measured. Twenty-four hours after surgery, the absorbance value of LoVo cells at 10% serum concentration from PEA was decreased when compared with SGA.0.302.0.026) vs 0.391.0.066), p = 0.005 The inhibitory rate of LoVo cells at 10% serum concentration from PEA was higher than that from SGA.p = 0.004) 24 h after surgery. The number of invasive LoVo cells at 10% serum concentration from PEA was reduced when compared with SGA.44.4) vs 62.4), p < 0.001 Exposure of LoVo cells to postoperative serum from patients receiving PEA led to a higher luminescence ratio.apoptosis) than those receiving SGA.0.36.0.04) vs 0.27.0.05), p < 0.001 Serum from patients receiving PEA for colon cancer surgery inhibited proliferation and invasion of LoVo cells and induced apoptosis in vitro more than that from patients receiving SGA. Anaesthetic technique might influence the serum milieu in a way that affects cancer cell biology and, thereby, tumour metastastasis.

Intralipid in Cancer treatment

We have developed a new strategy to temporarily blunt the reticuloendothelial system uptake of nanodrugs, a major challenge for nanodrug delivery and causing off-target toxicities, using an FDA approved nutrition supplement, Intralipid. We have tested our methodology in rats using an experimental platinum-containing anti-cancer nanodrug and three FDA approved nanodrugs, Abraxane, Marqibo, and Onivyde, to determine their toxicities in liver, spleen, and kidney, with and without the addition of Intralipid. Our method illustrates its potentials to deliver nanodrugs with an increase in the bioavailability and a decrease in toxicities. Our study shows that Intralipid treatment exhibits no harmful effect on tumor growing and no negative effect on the anti-tumor efficacy of the platinum-containing nanodrug, as well as animal survival rate in a HT-29 xenograft mouse model. Our methodology could also be a valuable complement/supplement to the "stealth" strategies. Our approach is a general one applicable to any approved and in-development nanodrugs without additional modification of the nanodrugs, thus facilitating its translation to clinical settings.

The aim of this study was to prepare and characterize a new nanocarrier for oral delivery of tamoxifen citrate.TMC) as a lipophilic oral administrated drug. This drug has low oral bioavailability due to its low aqueous solubility. To enhance the solubility of this drug, the microemulsion system was applied in form of oil-in-water. Sesame oil and Tween 80 were used as drug solvent oil and surfactant, respectively. Two different formulations were prepared for this purpose. The first formulation contained edible glycerin as co-surfactant and the second formulation contained Span 80 as a mixed surfactant. The results of characterization showed that the mean droplet size of drug-free samples was in the range of 16.64-64.62nm with a PDI value of <0.5. In a period of 6months after the preparation of samples, no phase sedimentation was observed, which confirmed the high stability of samples. TMC with a mass ratio of 1% was loaded in the selected samples. No significant size enlargement and drug precipitation were observed 6months after drug loading. In addition, the drug release profile at experimental environments in buffers with pH=7.4 and 5.5 showed that in the first 24h, 85.79 and 100% of the drug were released through the first formulation and 76.63 and 66.42% through the second formulation, respectively. The in-vivo results in BALB/c female mice showed that taking microemulsion form of drug caused a significant reduction in the growth rate of cancerous tumor and weight loss of the mice compared to the consumption of commercial drug tablets. The results confirmed that the new formulation of TMC could be useful for breast cancer treatment.

Paclitaxel.PTX) is a effectively chemotherapeutic agent which is extensively able to treat the non-small cell lung, pancreatic, breast and other cancers. But it is a practically insoluble drug with water solubility less than 1 µg/mL, which restricts its therapeutic application. To overcome the problem, hyaluronic acid-complexed paclitaxel nanoemulsions.HPNs) were prepared by ionic complexation of paclitaxel.PTX) nanoemulsions and hyaluronic acid.HA) to specifically target non-small cell lung cancer. HPNs were composed of DL-α-tocopheryl acetate, soybean oil, polysorbate 80, ferric chloride, and HA and fabricated by high-pressure homogenization. The HPNs were 85.2 ± 7.55 nm in diameter and had a zeta potential of -35.7 ± 0.25 mV. The encapsulation efficiency was almost 100%, and the PTX content was 3.0 mg/mL. We assessed the in vivo antitumor efficacy of the HPNs by measuring changes in tumor volume and body weight in nude mice transplanted with CD44-overexpressing NCI-H460 xenografts and treated with a bolus dose of saline, Taxol®, PTX nanoemulsions.PNs), or HPNs at a dose of 25 mg/kg. Suppression of cancer cell growth was higher in the PN- and HPN-treated groups than in the Taxol® group. In particular, HPN treatment dramatically inhibited tumor growth, likely because of the specific tumor-targeting affinity of HA for CD44-overexpressed cancer cells. The loss of body weight and organ weight did not vary significantly between the groups. It is suggest that HPNs should be used to effective nanocarrier system for targeting delivery of non-small cell lung cancer overexpressing CD44 and high solubilization of poorly soluble drug.

The aim of this study is to investigate using nanoemulsion formulations as drug-delivery vehicles of paclitaxel.PX), a poor water-soluble anticancer drug. Two commercially available nanoemulsion fat formulations.Clinoleic 20% and Intralipid 20%) were loaded with PX and characterised based on their size, zeta potential, pH and loading efficiency. The effect of formulation on the cytotoxicity of PX was also evaluated using MTT assay. The droplet size of the Clinoleic emulsion increased from 254.1nm to 264.7nm when paclitaxel.6mg/ml) was loaded into the formulation, compared to the drug-free formulation. Similarly, the droplet size of Intralipid increased from 283.3 to 294.6nm on inclusion of 6mg/ml paclitaxel. The Polydispersity Indexes.PDIs) of all the nanoemulsion formulations.Clinoleic and Intralipid) were less than 0.2 irrespective of paclitaxel concentration indicating that all nanoemulsion formulations used were homogeneously sized. The pH range for the Clinoleic formulations.7.1-7.5) was slightly higher than that of the Intralipid formulations.6.5-6.9 The zeta potential of linoleic had a greater negative value than that of Intralipid. Loading efficiencies for paclitaxel were 70.4-80.2% and 44.2-57.4% for Clinoleic and Intralipidformulations, respectively. Clinoleic loaded with paclitaxel decreased the viability of U87-MG cell to 6.4±2.3%, compared to Intralipid loaded with paclitaxel.21.29±3.82% Both nanoemulsions were less toxic to the normal glial cells.SVG-P12), decreasing the cell viability to 25-35%. This study suggests that nanoemulsions are useful and potentially applicable vehicles of paclitaxel for treatment of glioma.

Nanoemulsions.NE) are one of the robust delivery tools for drugs due to their higher stability and efficacy.

The purpose of present investigation is to develop stable, effective and safe NE of docetaxel.DTX

Soybean oil, lecithin, Pluronic F68, PEG 4000 and ethanol were employed as excipients and NEs were prepared by hot homogenization followed by ultra-sonication. NEs were optimized and investigated for different in vitro and in vivo parameters viz. droplet size, poly dispersity index, charge; zeta potential, drug content and in vitro drug release, in vitro cytotoxicity, in vitro cell uptake and acute toxicity. Transmission electron microscopy was performed to study morphology and structure of NEs. Stability studies of the optimized formulation were performed.

Droplet size, poly dispersity index, zeta potential, drug content and in vitro drug release were found to be 233.23 ± 4.3 nm, 0.24 ± 0.010, -43.66 ± 1.9 mV, 96.76 ± 1.5%, 96.25 ± 2.1%, respectively. NE F11 exhibited higher cell uptake.2.83 times than control) and strong cytotoxic activity against MCF-7 cancer cells.IC50; 13.55 ± 0.21 µg/mL at 72 h) whereas no toxicity or necrosis was observed with liver and kidney tissues of mice at a dose of 20 mg/kg. Transmission electron microscopy ensured formation of poly-dispersed and spherical droplets in nanometer range. NE F11.values indicated above) was selected as the optimized formulation based on the aforesaid parameters.

Conclusively, stable, effective and safe NE was developed which might be used as an alternative DTX therapy.

Platinum.Pt) drugs are the most potent and commonly used anti-cancer chemotherapeutics. Nanoformulation of Pt drugs has the potential to improve the delivery to tumors and reduce toxic side effects. A major challenge for translating nanodrugs to clinical settings is their rapid clearance by the reticuloendothelial system.RES), hence increasing toxicities on off-target organs and reducing efficacy. We are reporting that an FDA approved parenteral nutrition source, Intralipid 20%, can help this problem. A dichloro.1, 2-diaminocyclohexane) platinum.II)-loaded and hyaluronic acid polymer-coated nanoparticle.DACHPt/HANP) is used in this study. A single dose of Intralipid.2 g/kg, clinical dosage) is administrated [intravenously.i. v.), clinical route] one hour before i.v. injection of DACHPt/HANP. This treatment can significantly reduce the toxicities of DACHPt/HANP in liver, spleen, and, interestingly, kidney. Intralipid can decrease Pt accumulation in the liver, spleen, and kidney by 20.4%, 42.5%, and 31.2% at 24-hr post nanodrug administration, respectively. The bioavailability of DACHPt/HANP increases by 18.7% and 9.4% during the first 5 and 24 hr, respectively.

A lipid emulsion composed of soybean oil.long-chain triglycerides, LCT), medium-chain triglycerides.MCT) and n-3 poly-unsaturated fatty acids.PUFAs) was evaluated for immune-modulation efficacy, safety, and tolerance in patients undergoing major surgery for gastric and colorectal cancer.

In a prospective, randomized, double-blind study, 99 patients with gastric and colorectal cancer receiving elective surgery were recruited and randomly assigned to either the study group, receiving the n-3 PUFAs enriched intravenous fat emulsion.IVFE), or the control group, receiving a lipid emulsion comprised of soybean oil and MCTs.0.8 - 1.5 g · kg-1 · day-1) as part of total parenteral nutrition.TPN) regimen from surgery.day -1) up to post-operative day 7. Safety and efficacy parameters were assessed on day -1 and post-operative visits on day 1, 3, and 7. Adverse events were documented daily and compared between the groups.

Pro-inflammatory markers, laboratory parameters, and adverse events did not differ prominently between the 2 groups, with the exception of net changes.day 7 minus day -1) of free fatty acids.FFAs), triglyceride, and high-density lipoprotein.HDL Net decrease of FFAs was remarkably higher in the study group, while the net increase of triglyceride and decrease of HDL was significantly lower.

The n-3 PUFA-enriched IVFE showed improvements in lipid metabolism. In respect of efficacy, safety and tolerance both IVFE were comparable. In patients with severe stress, there is an inflammation-attenuating effect of n-3 PUFAs. Further, adequately powered clinical trials will be necessary to address this question in postsurgical GI cancer patients.

Prostate cancer is the second leading cause of male deaths due to cancer in the United States. Hydrogenated vegetable oils have been suspected of inducing adverse health effects, including atherosclerosis and cancer. Here we report that a selectively hydrogenated soybean oil.SHSO) containing a high quantity of conjugated linoleic acids showed remarkably strong anticarcinogenic activity against prostate cancerin the rat model.Copenhagen rats with MAT-LyLu syngeneic rat prostate cancer cells) study in vivo and human prostate carcinoma cell lines studies in vitro, as compared with native soybean oil. A 5% dietary supplementation with SHSO inhibited the growth of prostate cancer by 80% in vivo. The TUNEL method and immunohistochemical staining assays of bax, bcl-2, and survivin clearly showed that SHSO induced prostate cancer cell apoptosis in the tested rats. DNA fragmentation analysis in vitro further confirmed the apoptotic activity of SHSO on the MAT-LyLu prostate cancer cells. The SHSO also showed strong cytotoxicity on human prostate cancer cells.DU145 and PC3 This represents the first report demonstrating the significant anticancer activities of hydrogenated vegetable oils at low levels of dietary supplementation.

This study has been undertaken to investigate if the intravenous.i.v.) infusion of fat emulsions may be associated with impairment of some immunological functions thus increasing the risk of septic complications. Fifteen malnourished patients with advanced gastric or esophageal cancer received for 2 weeks preoperatively and 1 week after surgery an isocaloric and isonitrogenous TPN treatment with Intralipid.group A: n=8) or glucose alone.group B: n=7) as energy substrate. Cluster analysis of 11 nutritional parameters and some tests of the humoral and cellular immunity.IgG, IgM, C3c, Factor B; polymorphonuclear.PMN) cells, total lymphocytes, T and B lymphocyte counts; 'in vitro' PMN chemotaxis, adherence to nylon fibers, phagocytosis of latex particles) were sequentially determined. The incidence and severity of post-operative infections were investigated and a 'sepsis score' was calculated for each patient. Pre- and postoperative TPN were not associated with an improvement of the nutritional status. The humoral and cellular immune parameters showed the same behaviour in patients receiving Intralipid and in controls. The chemotactic activity of PMN cells was constantly normal, granulocyte adherence fluctuated below the normality range in controls, whereas phagocytosis of latex was similar in both groups. Post-operative infectious episodes were less severe in patients receiving Intralipid. Our results do not confirm that Intralipid adversely affects some aspects of the humoral and cellular immune response.

Mitochondria in Cancer

Mitochondria, known for more than a century as the energy powerhouse of a cell, represent key intracellular signaling hub that are emerging as important determinants of several aspects of cancer development and progression, including metabolic reprogramming, acquisition of metastatic capability, and response to chemotherapeutic drugs. The majority of cancer cells harbors somatic mutations in the mitochondrial genome.mtDNA) and/or alterations in the mtDNA content, leading to mitochondrial dysfunction. Decreased mtDNA content is also detected in tumor-initiating cells, a subpopulation of cancer cells that are believed to play an integral role in cancer recurrence following chemotherapy. Although mutations in mitochondrial genes are common in cancer cells, they do not shut down completely the mitochondrial energy metabolism and functionality. Instead, they promote rewiring of the bioenergetics and biosynthetic profile of a cancer cell through a mitochondria-to-nucleus signaling activated by "dysfunctional" mitochondria that results in changes in transcription and/or activity of cancer-related genes and signaling pathways. Different cancer cell types may undergo different bioenergetic changes, some to more glycolytic and some to more oxidative. These different metabolic signatures may coexist within the same tumor mass.intra-tumor heterogeneity In this review we describe the current understanding of mitochondrial dysfunction in the context of cancer chemoresistance with special attention to the role of mtDNA alterations. We put emphasis on potential therapeutic strategies targeting different metabolic events specific to cancercells, including glycolysis, glutaminolysis, oxidative phosphorylation, and the retrograde signaling, to prevent chemoresistance. We also highlight novel genome-editing strategies aimed at "correcting" mtDNA defects in cancer cells. We conclude on the importance of considering intratumor metabolic heterogeneity to develop effective metabolism-based cancer therapy that can overcome chemoresistance.

Mitochondria are bioenergetic, biosynthetic, and signaling organelles that are integral in stress sensing to allow for cellular adaptation to the environment. Therefore, it is not surprising that mitochondria are important mediators of tumorigenesis, as this process requires flexibility to adapt to cellular and environmental alterations in addition to cancer treatments. Multiple aspects of mitochondrial biology beyond bioenergetics support transformation, including mitochondrial biogenesis and turnover, fission and fusion dynamics, cell death susceptibility, oxidative stress regulation, metabolism, and signaling. Thus, understanding mechanisms of mitochondrial function during tumorigenesis will be critical for the next generation of cancer therapeutics.

Decades ago, Otto Warburg observed that cancers ferment glucose in the presence of oxygen, suggesting that defects in mitochondrial respiration may be the underlying cause of cancer. We now know that the genetic events that drive aberrant cancer cell proliferation also alter biochemical metabolism, including promoting aerobic glycolysis, but do not typically impair mitochondrial function. Mitochondria supply energy; provide building blocks for new cells; and control redox homeostasis, oncogenic signaling, innate immunity, and apoptosis. Indeed, mitochondrial biogenesis and quality control are often upregulated in cancers. While some cancers have mutations in nuclear-encoded mitochondrial tricarboxylic acid.TCA) cycle enzymes that produce oncogenic metabolites, there is negative selection for pathogenic mitochondrial genome mutations. Eliminating mtDNA limits tumorigenesis, and rare human tumors with mutant mitochondrial genomes are relatively benign. Thus, mitochondria play a central and multifunctional role in malignant tumor progression, and targeting mitochondria provides therapeutic opportunities.

Until recently, the dual roles of mitochondria in ATP production.bioenergetics) and apoptosis.cell life/death decision) were thought to be separate. New evidence points to a more intimate link between these two functions, mediated by the remodeling of the mitochondrial ultrastructure during apoptosis. While most of the key molecular players that regulate this process have been identified.primarily membrane proteins), the exact mechanisms by which they function are not yet understood. Because resistance to apoptosis is a hallmark of cancer, and because ultimately all chemotherapies are believed to result directly or indirectly in induction of apoptosis, a better understanding of the biophysical processes involved may lead to new avenues for therapy.

Contrary to conventional wisdom, functional mitochondria are essential for the cancer cell. Although mutations in mitochondrial genes are common in cancer cells, they do not inactivate mitochondrial energy metabolism but rather alter the mitochondrial bioenergetic and biosynthetic state. These states communicate with the nucleus through mitochondrial 'retrograde signalling' to modulate signal transduction pathways, transcriptional circuits and chromatin structure to meet the perceived mitochondrial and nuclear requirements of the cancer cell. Cancer cells then reprogramme adjacent stromal cells to optimize the cancer cell environment. These alterations activate out-of-context programmes that are important in development, stress response, wound healing and nutritional status.

Mitochondria are indispensable for energy metabolism, apoptosis regulation, and cell signaling. Mitochondria in malignant cells differ structurally and functionally from those in normal cells and participate actively in metabolic reprogramming. Mitochondria in cancer cells are characterized by reactive oxygen species.ROS) overproduction, which promotes cancer development by inducing genomic instability, modifying gene expression, and participating in signaling pathways. Mitochondrial and nuclear DNA mutations caused by oxidative damage that impair the oxidative phosphorylation process will result in further mitochondrial ROS production, completing the "vicious cycle" between mitochondria, ROS, genomic instability, and cancer development. The multiple essential roles of mitochondria have been utilized for designing novel mitochondria-targeted anticancer agents. Selective drug delivery to mitochondria helps to increase specificity and reduce toxicity of these agents. In order to reduce mitochondrial ROS production, mitochondria-targeted antioxidants can specifically accumulate in mitochondria by affiliating to a lipophilic penetrating cation and prevent mitochondria from oxidative damage. In consistence with the oncogenic role of ROS, mitochondria-targeted antioxidants are found to be effective in cancer prevention and anticancer therapy. A better understanding of the role played by mitochondria in cancer development will help to reveal more therapeutic targets, and will help to increase the activity and selectivity of mitochondria-targeted anticancer drugs.

The long-recognized fact that oxidative stress within mitochondria is a hallmark of mitochondrial dysfunction has stimulated the development of mitochondria-targeted antioxidant therapies. Melatonin should be included among the pharmacological agents able to modulate mitochondrial functions in cancer, given that a number of relevant melatonin-dependent effects are triggered by targeting mitochondrial functions. Indeed, melatonin may modulate the mitochondrial respiratory chain, thus antagonizing the cancer highly glycolytic bioenergetic pathway of cancer cells. Modulation of the mitochondrial respiratory chain, together with Ca2+ release and mitochondrial apoptotic effectors, may enhance the spontaneous or drug-induced apoptotic processes. Given that melatonin may efficiently counteract the Warburg effect while stimulating mitochondrial differentiation and mitochondrial-based apoptosis, it is argued that the pineal neurohormone could represent a promising new perspective in cancer treatment strategy.

This review focuses on the selective antiproliferative and cytotoxic effects of mitochondria-targeted therapeutics.MTTs) in cancer cells. Emerging research reveals a key role of mitochondrial respiration on tumor proliferation. Previously, a mitochondria-targeted nitroxide was shown to selectively inhibit colon cancer cell proliferation at submicromolar levels. This review is centered on the therapeutic use of MTTs and their bioenergetic profiling in cancercells. Triphenylphosphonium cation conjugated to a parent molecule.e.g., vitamin-E or chromanol, ubiquinone, and metformin) via a linker alkyl chain is considered an MTT. MTTs selectively and potently inhibit proliferation of cancer cells and, in some cases, induce cytotoxicity. MTTs inhibit mitochondrial complex I activity and induce mitochondrial stress in cancer cells through generation of reactive oxygen species. MTTs in combination with glycolytic inhibitors synergistically inhibit tumor cell proliferation.

Warburg's hypothesis that cancer cells take up a lot of glucose in the presence of ambient oxygen but convert pyruvate into lactate due to impaired mitochondrial function led to the misconception that cancer cells rely on glycolysis as their major source of energy. Most recent 13C-based metabolomic studies, including in cancer patients, indicate that cancer cells may also fully oxidize glucose. In addition to glucose-derived pyruvate, lactate, fatty acids and amino acids supply substrates to the TCA cycle to sustain mitochondrial metabolism. Here, we discuss how the metabolic flexibility afforded by these multiple mitochondrial inputs allows cancer cells to adapt according to the availability of the different fuels and the microenvironmental conditions such as hypoxia and acidosis. In particular, we focused on the role of the TCA cycle in interconnecting numerous metabolic routes in order to highlight metabolic vulnerabilities that represent attractive targets for a new generation of anticancer drugs.

Mitochondria play a key role in ATP generation, redox homeostasis and regulation of apoptosis. Due to the essential role of mitochondria in metabolism and cell survival, targeting mitochondria in cancer cells is considered as an attractive therapeutic strategy. However, metabolic flexibility in cancer cells may enable the upregulation of compensatory pathways, such as glycolysis to support cancer cell survival when mitochondrial metabolism is inhibited. Thus, compounds capable of both targeting mitochondria and inhibiting glycolysis may be particularly useful to overcome such drug-resistant mechanism.

Cancer can be characterized as a state of multifaceted cellular deregulation including control of proliferation and bioenergetics. The latter involves in particular mitochondria, the site of the generation of ATP, essential for the proper cellular function.including proliferation Mitochondria also contain a variety of proteins that are necessary for the induction/promotion, as well as for the prevention of cell death. Therefore, mitochondria are pivotal in deciding the fate of a cell. In cancer, mitochondria are dysfunctional, which was observed as early as in the 1930s by Otto Warburg. Due to the central role of mitochondria, these organelles, endowed with its own DNA, are a focus of research as possible "culprits" for the malignancy of cancer cells.or at least contributing to this phenotype) and, importantly, as emerging targets for anticancer therapy.

Defective oxidative phosphorylation has a crucial role in the attenuation of mitochondrial function, which confers therapy resistance in cancer. Various factors, including endogenous heat shock proteins.HSPs) and exogenous agents such as dichloroacetate, restore respiratory and other physiological functions of mitochondria in cancer cells. Functional mitochondria might ultimately lead to the restoration of apoptosis in cancer cells that are refractory to current anticancer agents. Here, we summarize the key reasons contributing to mitochondria dysfunction in cancer cells and how restoration of mitochondrial function could be exploited for cancer therapeutics.

Macroautophagy.autophagy hereafter) captures intracellular proteins and organelles and degrades them in lysosomes. The degradation breakdown products are released from lysosomes and recycled into metabolic and biosynthetic pathways. Basal autophagy provides protein and organelle quality control by eliminating damaged cellular components. Starvation-induced autophagy recycles intracellular components into metabolic pathways to sustain mitochondrial metabolic function and energy homeostasis. Recycling by autophagy is essential for yeast and mammals to survive starvation through intracellular nutrient scavenging. Autophagy suppresses degenerative diseases and has a context-dependent role in cancer. In some models, cancer initiation is suppressed by autophagy. By preventing the toxic accumulation of damaged protein and organelles, particularly mitochondria, autophagy limits oxidative stress, chronic tissue damage, and oncogenic signaling, which suppresses cancer initiation. This suggests a role for autophagy stimulation in cancer prevention, although the role of autophagy in the suppression of human cancer is unclear. In contrast, some cancers induce autophagy and are dependent on autophagy for survival. Much in the way that autophagy promotes survival in starvation, cancers can use autophagy-mediated recycling to maintain mitochondrial function and energy homeostasis to meet the elevated metabolic demand of growth and proliferation. Thus, autophagy inhibition may be beneficial for cancer therapy. Moreover, tumors are more autophagy-dependent than normal tissues, suggesting that there is a therapeutic window. Despite these insights, many important unanswered questions remain about the exact mechanisms of autophagy-mediated cancer suppression and promotion, how relevant these observations are to humans, and whether the autophagy pathway can be modulated therapeutically in cancer.

Mitochondria play important roles as energetic centers. Mutations in mitochondrial DNA.mtDNA) were found in several diseases, including cancers. Studies on cytoplasmic hybrids.cybrids) confirm that directed mutation introduced into mtDNA could be a reason for cancerinduction. Mitochondria could also be a factor linking cancer transformation and progression. The importance of mitochondria in cancer also confirms their involvement in the resistance to treatment. Resistance to treatment of cancer cells can frequently be a reason for glycolysis acceleration. It could be explained by cancer cells' high proliferation index and high energy request. The involvement of mitochondria in metabolic disturbances of several metabolic diseases, including cancers, was reported. These data confirm that cancer induction, as well as cancer progression, could have metabolic roots. The aberrant products observed in prostate cells involved in the Krebs cycle could promote cancer progression. These multiple relationships between alterations on a genetic level translated into disturbances in cellular metabolism and their potential relation with epigenetic control of gene expression make cancerogenesis more complicated and prognoses' success in studies on cancer etiology more distant in time.

Mitochondria have a well-recognized role in the production of ATP and the intermediates needed for macromolecule biosynthesis, such as nucleotides. Mitochondria also participate in the activation of signaling pathways. Overall, accumulating evidence now suggests that mitochondrial bioenergetics, biosynthesis and signaling are required for tumorigenesis. Thus, emerging studies have begun to demonstrate that mitochondrial metabolism is potentially a fruitful arena for cancer therapy.

Under normal conditions, basal levels of wild-type p53 promote mitochondrial function through multiple mechanisms. Remarkably, some missense mutations of p53, in contrast to the null state, can result in the retention of its metabolic activities. These effects are particularly prominent in the mitochondria and demonstrate a functional role for mutant p53 in cancer metabolism. This review summarizes accumulating data on the mechanisms by which p53 missense mutations can regulate mitochondrial metabolism and promote the viability and survival of both normal and cancer cells, thus acting as a double edged sword for the host. Greater understanding of these mechanisms may provide insights for developing new treatment or preventive strategies against cancer.

Mitochondrial structural and functional integrity defines the health of a cell by regulating cellular metabolism. Thus, mitochondria play an important role in both cell proliferation and cell death. Cancer cells are metabolically altered compared to normal cells for their ability to survive better and proliferate faster. Resistance to apoptosis is an important characteristic of cancer cells and given the contribution of mitochondria to apoptosis, it is imperative that mitochondria could behave differently in a tumor situation. The other feature associated with cancer cells is the Warburg effect, which engages a shift in metabolism. Although the Warburg effect often occurs in conjunction with dysfunctional mitochondria, the relationship between mitochondria, the Warburg effect, and cancer cell metabolism is not clearly decoded. Other than these changes, several mitochondrial gene mutations occur in cancer cells, mitochondrial biogenesis is affected and mitochondria see structural and functional variations. In cancer pharmacology, targeting mitochondria and mitochondria associated signaling pathways to reduce tumor proliferation is a growing field of interest.

Mitochondria are essential intracellular organelles that regulate energy metabolism, cell death, and signaling pathways that are important for cell proliferation and differentiation. Therefore, mitochondria are fundamentally implicated in cancer biology, including initiation, growth, metastasis, relapse, and acquired drug resistance. Based on these implications, mitochondria have been proposed as a major therapeutic target for cancer treatment. In addition to classical view of mitochondria in cancer biology, recent studies found novel pathophysiological roles of mitochondria in cancer. Recent concepts of mitochondrial roles in cancer biology including mitochondrial DNA mutation and epigenetic modulation, energy metabolism reprogramming, mitochondrial channels, involvement in metastasis and drug resistance, and cancer stem cells.

Cancer is among the leading causes of death worldwide, and the number of new cases continues to rise. Despite recent advances in diagnosis and therapeutic strategies, millions of cancer-related deaths occur, indicating the need for better therapies and diagnostic strategies. Mitochondria and metabolic alterations have been recognized as important for cancer progression. However, a more precise understanding of how to manipulate mitochondria-related processes for cancer therapy remains to be established. Mitochondria are highly dynamic organelles which continually fuse and divide in response to diverse stimuli. Participation in the aforementioned processes requires a precise regulation at many levels that allows the cell to couple mitochondrial activity to nutrient availability, biosynthetic demands, proliferation rates, and external stimuli. The many functions of these organelles are intimately linked to their morphology. Recent evidence suggests an important link between mitochondrial morphology and disease, including neurodegenerative, inflammatory diseases and cancer.

LncRNAs, as new players in the old battle against cancer, are significant components of gene regulatory networks. Mitochondria-associated lncRNAs have newly been discovered to work in concert with transcription factors and epigenetic regulators to modulate mitochondrial gene expression and mitochondrial function. Many mitochondria-associated lncRNAs regulate mitochondrial biosynthesis, bioenergetics, apoptosis and possibly govern the cross-talk of mitochondria with nuclei. The complexity of mitochondria-associated lncRNAs is now just starting to envisage. We collected available evidence that reinforces the importance of mitochondria-associated lncRNA in cancer metabolism, apoptosis, and cell senescence. For the non-exhaustive list of mitochondria-associated lncRNAs, we identified 18 lncRNAs in total.mitochondria-encoded lncRNAs or nuclei encoded mitochondria function associated lncRNAs) as emerging new players in cancer mitochondrial function. As lncRNAs exhibit cancer-type-specific expression patterns, they are attractive targets for selective therapeutic interventions. Manipulation of their function may thus represent a valuable strategy for future cancer treatment.

Mitophagy, the selective engulfment and clearance of mitochondria, is essential for the homeostasis of a healthy network of functioning mitochondria and prevents excessive production of cytotoxic reactive oxygen species from damaged mitochondria. The mitochondrially targeted PTEN-induced kinase-1.PINK1) and the E3 ubiquitin ligase Parkin are well-established synergistic mediators of the mitophagy of dysfunctional mitochondria. This pathway relies on the ubiquitination of a number of mitochondrial outer membrane substrates and subsequent docking of autophagy receptor proteins to selectively clear mitochondria. There are also alternate Parkin-independent mitophagy pathways mediated by BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 and Nip-3 like protein X as well as other effectors. There is increasing evidence that ablation of mitophagy accelerates a number of pathologies. Familial Parkinsonism is associated with loss-of-function mutations in PINK1 and Parkin. A growing number of studies have observed a correlation between impaired Parkin activity and enhanced cancer development, leading to the emerging concept that Parkin activity, or mitophagy in general, is a tumour suppression mechanism..

Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the cell and mitochondrial membrane potentials, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. We discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes, and sensors, and examples of mitochondrial targeting of bioactive compounds.

Mitochondria play fundamental roles in the regulation of life and death of eukaryotic cells. They mediate aerobic energy conversion through the oxidative phosphorylation.OXPHOS) system, and harbor and control the intrinsic pathway of apoptosis. As a descendant of a bacterial endosymbiont, mitochondria retain a vestige of their original genome.mtDNA), and its corresponding full gene expression machinery. Proteins encoded in the mtDNA, all components of the multimeric OXPHOS enzymes, are synthesized in specialized mitochondrial ribosomes.mitoribosomes Mitoribosomes are therefore essential in the regulation of cellular respiration. Additionally, an increasing body of literature has been reporting an alternative role for several mitochondrial ribosomal proteins as apoptosis-inducing factors. No surprisingly, the expression of genes encoding for mitoribosomal proteins, mitoribosome assembly factors and mitochondrial translation factors is modified in numerous cancers, a trait that has been linked to tumorigenesis and metastasis.

Mitochondria, which are multi-functional, have been implicated in cancer initiation, progression, and metastasis due to metabolic alterations in transformed cells. Mitochondria are involved in the generation of energy, cell growth and differentiation, cellular signaling, cell cycle control, and cell death. To date, the mitochondrial basis of cancer disparities is unknown. Due to maternal inheritance and ethnic-based diversity, the mitochondrial genome.mtDNA) contributes to inherited racial disparities. In people of African ancestry, several germline, population-specific haplotype variants in mtDNA as well as depletion of mtDNA have been linked to cancer predisposition and cancer disparities. Indeed, depletion of mtDNA and mutations in mtDNA or nuclear genome.nDNA)-encoded mitochondrial proteins lead to mitochondrial dysfunction and promote resistance to apoptosis, the epithelial-to-mesenchymal transition, and metastatic disease, all of which can contribute to cancer disparity and tumor aggressiveness related to racial disparities. Ethnic differences at the level of expression or genetic variations in nDNA encoding the mitochondrial proteome, including mitochondria-localized mtDNA replication and repair proteins, miRNA, transcription factors, kinases and phosphatases, and tumor suppressors and oncogenes may underlie susceptibility to high-risk and aggressive cancers found in African population and other ethnicities. The mitochondrial retrograde signaling that alters the expression profile of nuclear genes in response to dysfunctional mitochondria is a mechanism for tumorigenesis. In ethnic populations, differences in mitochondrial function may alter the cross talk between mitochondria and the nucleus at epigenetic and genetic levels, which can also contribute to cancer health disparities. Targeting mitochondrial determinants and mitochondrial retrograde signaling could provide a promising strategy for the development of selective anticancer therapy for dealing with cancer disparities. Further, agents that restore mitochondrial function to optimal levels should permit sensitivity to anticancer agents for the treatment of aggressive tumors that occur in racially diverse populations and hence help in reducing racial disparities.

Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells.CSCs), a.k.a., tumor-initiating cells.TICs We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of "stemness", independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point - a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known "side-effect", which could be harnessed instead as a "therapeutic effect". Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types.breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma.brain) These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin.intended to target cancer-associated infections, but not cancercells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.

Deregulated cellular energetics was one of the cancer hallmarks. Several underlying mechanisms of deregulated cellular energetics are associated with mitochondrial dysfunction caused by mitochondrial DNA mutations, mitochondrial enzyme defects, or altered oncogenes/tumor suppressors. In this review, we summarize the current understanding about the role of mitochondrial dysfunction in cancerprogression. Point mutations and copy number changes are the two most common mitochondrial DNA alterations in cancers, and mitochondrial dysfunction induced by chemical depletion of mitochondrial DNA or impairment of mitochondrial respiratory chain in cancercells promotes cancer progression to a chemoresistance or invasive phenotype. Moreover, defects in mitochondrial enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, are associated with both familial and sporadic forms of cancer. Deregulated mitochondrial deacetylase sirtuin 3 might modulate cancer progression by regulating cellular metabolism and oxidative stress. These mitochondrial defects during oncogenesis and tumor progression activate cytosolic signaling pathways that ultimately alter nuclear gene expression, a process called retrograde signaling. Changes in the intracellular level of reactive oxygen species, Ca(2+), or oncometabolites are important in the mitochondrial retrograde signaling for neoplastic transformation and cancer progression. In addition, altered oncogenes/tumor suppressors including hypoxia-inducible factor 1 and tumor suppressor p53 regulate mitochondrial respiration and cellular metabolism by modulating the expression of their target genes. We thus suggest that mitochondrial dysfunction plays a critical role in cancer progression and that targeting mitochondrial alterations and mitochondrial retrograde signaling might be a promising strategy for the development of selective anticancer therapy.

Mitochondria, the energy supply factories for cell-life activities, play important roles in controlling epigenetics, differentiation and initiation, and the execution of apoptosis. These functions of the mitochondria contribute to cell adaptation to challenging microenvironment conditions. In past decades, mitochondrial malfunction has been revealed to be closely related to the occurrence and development of a variety of human disorders, including cancer and multiple neurodegenerative diseases. The disturbance of the mitochondrial genome.mtDNA) or mitochondrial vital functions, e.g., the production of adenosine triphosphate.ATP) and the generation of reactive oxygen species.ROS), can potentially be involved in disease pathogenesis. Recent research has shown that the precise monitoring of mitochondrial environments can provide potential directions for cancer diagnosis. Furthermore, mitochondrial-targeted cancer treatment exhibits unparalleled superiority for enhanced tumor therapy. Therefore, in this review, we focus on mitochondrial-based cancer diagnosis via monitoring mitochondrial respiration or mitophagy. Current approaches using mitochondrial-based cancer treatments, including targeting mitochondrial ATP, mitochondrial membrane permeability, and mitochondrial ROS levels and mtDNA.

Mitochondria-shaping proteins control the dynamic equilibrium between fusion and fission of the mitochondrial network. Their balance is strictly required to regulate various processes, including the quality of mitochondria, cell metabolism, cell death, proliferation and cell migration. Alterations in these processes are frequently encountered in cancer, during both its onset and later progression, as evidence emerge connecting alterations in mitochondrial dynamics with cancer development. In recent years, novel therapeutic approaches to fight against different human tumors aim at exploiting the immune system's ability to specifically recognize tumor antigens, thus killing malignant cells in a process named immune-surveillance. Interestingly, data are accumulating on the role that mitochondrial dynamics play also for the correct function of both the innate and the adaptive immune system.

Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.

At the beginning of the twentieth century, Otto Warburg demonstrated that cancer cells have a peculiar metabolism. These cells preferentially utilise glycolysis for energetic and anabolic purposes, producing large quantities of lactic acid. He defined this unusual metabolism "aerobic glycolysis". At the same time, Warburg hypothesised that a disruption of mitochondrial activities played a precise pathogenic role in cancer. Because of this so-called "Warburg effect", mitochondrial physiology and cellular respiration in particular have been overlooked in pathophysiological studies of cancer. Over time, however, many studies have shown that mitochondria play a fundamental role in cell death by apoptosis or necrosis. Moreover, metabolic enzymes of the Krebs cycle have also recently been recognised as oncosuppressors. Recently, a series of studies were undertaken to re-evaluate the role of oxidative mitochondrial metabolism in cancer cell growth and progression. Some of these data indicate that modulation of mitochondrial respiration may induce an arrest of cancer cell proliferation and differentiation.pseudodifferentiation) and/or or death, suggesting that iatrogenic manipulation of some mitochondrial activities may induce anticancer effects. Moreover, studying the role of mitochondria in cancer cell dedifferentiation/differentiation processes may allow further insight into the pathophysiology and therapy of so-called cancer stem cells.

Apoptosis is a form of programmed cell death that is critical for basic human development and physiology. One of the more important surprises in cell biology in the last two decades is the extent to which mitochondria represent a physical point of convergence for many apoptosis-inducing signals in mammalian cells. Mitochondria not only adjudicate the decision of whether or not to commit to cell death, but also release toxic proteins culminating in widespread proteolysis, nucleolysis, and cell engulfment. Interactions among BCL-2 family proteins at the mitochondrial outer membrane control the release of these toxic proteins and, by extension, control cellular commitment to apoptosis. This pathway is particularly relevant to cancer treatment, as most cancer chemotherapies trigger mitochondrial-mediated apoptosis.

Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation. The genomic instability observed in tumor cells and all other recognized hallmarks of cancer are considered downstream epiphenomena of the initial disturbance of cellular energy metabolism. The disturbances in tumor cell energy metabolism can be linked to abnormalities in the structure and function of the mitochondria. When viewed as a mitochondrial metabolic disease, the evolutionary theory of Lamarck can better explain cancer progression than can the evolutionary theory of Darwin. Cancer growth and progression can be managed following a whole body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies. As each individual is a unique metabolic entity, personalization of metabolic therapy as a broad-based cancer treatment strategy will require fine-tuning to match the therapy to an individual's unique physiology.

Mitophagy is a selective mode of autophagy in which mitochondria are specifically targeted for degradation at the autophagolysosome. Mitophagy is activated by stresses such as hypoxia, nutrient deprivation, DNA damage, inflammation and mitochondrial membrane depolarization and plays a role in maintaining mitochondrial integrity and function. Defects in mitophagy lead to mitochondrial dysfunction that can affect metabolic reprogramming in response to stress, alter cell fate determination and differentiation, which in turn affects disease incidence and etiology, including cancer. Here, we discuss how different mitophagy adaptors and modulators, including Parkin, BNIP3, BNIP3L, p62/SQSTM1 and OPTN, are regulated in response to physiological stresses and deregulated in cancers. Additionally, we explore how these different mitophagy control pathways coordinate with each other. Finally, we review new developments in understanding how mitophagy affects stemness, cell fate determination, inflammation and DNA damage responses that are relevant to understanding the role of mitophagy in cancer.

Mitophagy, the selective degradation of mitochondria via the autophagic pathway, is a vital mechanism of mitochondrial quality control in cells. Mitophagy is responsible for the removal of malfunctioning or damaged mitochondria, which is essential for normal cellular physiology and tissue development. Pathways involved in the regulation of mitophagy, tumorigenesis, and cell death are overlapping in many cases and may be triggered by common upstream signals, which converge at the mitochondria. The failure to properly modulate mitochondrial turnover in response to oncogenic stresses can either stimulate or suppress tumorigenesis. Thus, the analysis of crosstalk among the processes of mitophagy, cell death and tumorigenesis is important for the identification of targets responsible for the stimulation of cell death and selective elimination of cancer cells.

The primacy of glucose derived from photosynthesis as an existential source of chemical energy across plant and animal phyla is universally accepted as a core principle in the biological sciences. In mammalian cells, initial processing of glucose to triose phosphate intermediates takes place within the cytosolic glycolytic pathway and terminates with temporal transport of reducing equivalents derived from pyruvate metabolism by membrane-associated respiratory complexes in the mitochondrial matrix. The intra-mitochondrial availability of molecular oxygen as the ultimate electron acceptor drives the evolutionary fashioned chemiosmotic production of ATP as a high-efficiency biological process. The mechanistic bases of carcinogenesis have demonstrated profound alteration of normative mitochondrial function, notably dysregulated respiratory processes. Accordingly, the classic Warburg effect functionally links aerobic glycolysis, aberrant production and release of lactate, and metabolic down-regulation of mitochondrial oxidative processes with the carcinogenetic phenotype. Aerobic fermentation by cancer cells may also represent a developmental re-emergence of an evolutionarily conserved early phenotype, which was "sidelined" with the emergence of mitochondrial oxidative phosphorylation as a primary mechanism for ATP production in normal cells. Regardless of state-dependent physiological status in mixed populations of cancer cells, it has been established that mitochondria are functionally linked to the initiation of cancer and its progression. Biochemical, molecular, and physiological differences in cancer cell mitochondria, notably mtDNA heteroplasmy and allele-specific expression of selected nuclear genes, may represent major focal points for novel targeting and elimination of cancer cells in metastatic disease afflicting human populations. To date, and despite considerable research efforts, the practical realization of advanced mitochondrial targeted therapies has not been forthcoming.

Tumour-initiating cells.TICs) play a pivotal role in cancer initiation, metastasis and recurrence, as well as in resistance to therapy. Therefore, development of drugs targeting TICs has become a focus of contemporary research. Mitochondria have emerged as a promising target of anti-cancer therapies due to their specific role in cancer metabolism and modulation of apoptotic pathways. Mitochondria of TICs possess special characteristics, some of which can be utilised to design drugs specifically targeting these cells.

Mitochondrial processes play an important role in tumor initiation and progression. We focus on three critical processes by which mitochondrial function may contribute to cancer: through alterations in glucose metabolism, the production of reactive oxygen species.ROS) and compromise of intrinsic apoptotic function. Alterations in cancer glucose metabolism include the Warburg effect, leading to a shift in metabolism away from aerobic respiration toward glycolysis, even when sufficient oxygen is present to support respiration. Such alterations in cellular metabolism may favor tumor cell growth by increasing the availability of biosynthetic intermediates needed for cellular growth and proliferation. Mutations in specific metabolic enzymes, namely succinate dehydrogenase, fumarate hydratase and the isocitrate dehydrogenases, have been linked to human cancer. Mitochondrial ROS may contribute to cancer via DNA damage and the activation of aberrant signaling pathways. ROS-dependent stabilization of the transcription factor hypoxia-inducible factor.HIF) may be a particularly important event for tumorigenesis. Compromised function of intrinsic apoptosis removes an important cellular safeguard against cancer and has been implicated in tumorigenesis, tumor metastasis, and chemoresistance. Each of the major mitochondrial processes is linked.

The area of mitochondrial genomics has undergone unprecedented growth over the past several years. With the advent of the age of omics, investigations have reached beyond the nucleus to encompass the close biological communication and finely coordinated interactions between mitochondria and their nuclear cell mate. Application of this holistic approach, to all metabolic interactions within the cell, is providing a more complete understanding of the molecular transformation of the cell from normal to malignant behavior, before histopathological indications are evident. The surging momentum in mitochondrial science, as it relates to cancer, is described in three progressive perspectives:.1) Past: the historical contributions to current directions of research;.2) Present: Contemporary findings, results and approaches to mitochondria and cancer, including the role of next generation sequencing and proteomics;.3) FUTURE: Based on the present body of knowledge, the potential assets and benefits of mitochondrial research are projected into the near future.

Mitochondrial dynamics encompasses processes associated with mitochondrial fission and fusion, affecting their number, degree of biogenesis, and the induction of mitophagy. These activities determine the balance between mitochondrial energy production and cell death programs. Processes governing mitochondrial dynamics are tightly controlled in physiological conditions and are often deregulated in cancer. Mitochondrial protein homeostasis, transcriptional regulation, and post-translational modification are among processes that govern the control of mitochondrial dynamics. Cancer cells alter mitochondrial dynamics to resist apoptosis and adjust their bioenergetic and biosynthetic needs to support tumor initiating and transformation properties including proliferation, migration, and therapeutic resistance.

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Tumour cell death is required for the clearance of malignant cells and is a vital part of the mechanism of natural tumour suppression. Cancer cells, having acquired multiple deregulated pathways involving several cellular oragenelles, are capable of disrupting these normally finely tuned processes thereby evading both physiological and therapeutic intervention. Although current available data indicate the dependence of successful tumour cell clearance on classical apoptotic pathways.intrinsic and/or extrinsic pathways), there is now evidence suggesting that alternative apoptotic and non-apoptotic pathways may effectively contribute to tumour cell death. The mitochondria, proteasomes, endoplasmic reticulum, Golgi apparatus, lysosomes and lysosome-related organelles of tumour cells exhibit a number of deregulations which have been identified as potential druggable targets for successful rational drug design and therapy.

Mitochondria are double membrane-enveloped organelles that play a central role in cellular metabolism, calcium homeostasis, redox signaling and cell fates. They function as main generators of ATP, metabolites for the construction of macromolecules and reactive oxygen species. In many cancer cells, mitochondria seem dysfunctional, manifested by a shift of energy metabolism from oxidative phosphorylation to active glycolysis and an increase in reactive oxygen species generation. These metabolic changes are often associated with upregulation of NAD(P)H oxidase. Importantly, the metabolic reprogramming in a cancer cell is mechanistically linked to oncogenic signals. Targeting mitochondria as a cancer therapeutic strategy has attracted much attention in the recent years and multiple review articles in this area have been published.

To provide examples of mitochondria-specific metabolic events that influence tumor cell biology, and of metabolism-related mitochondrial biomarkers and therapeutic targets in cancer cells.

Cancer cell mitochondria are rewired to optimally serve the cancer cell under various conditions of cellular stress. The nonexhaustive list of mitochondrial alterations that support cancer cell proliferation, survival, and/or progression includes upregulation of oxidative metabolism and use of alternative substrates, oncometabolites, increased superoxide production, mutated mitochondrial DNA, and altered mitochondrial morphology and dynamics. Potential therapeutic targets include fatty acid oxidation, voltage-dependent anion channel-1, the pyruvate dehydrogenase complex, and Complex I.

Some phenotypical traits, for example, chemoresistance and metastasis, are likely regulated by a fine-tuned balance between several metabolic processes and events that are upregulated in parallel and are also dependent on microenvironmental cues. Many metabolism-related mitochondrial biomarkers show prognostic value, but the biological interpretation of the data may be confounded by the overall metabolic status and context. Understanding metabolic regulation of stemness is important for targeting cancer stem cells. Therapeutic targeting of cancer cell mitochondria remains experimental but promising, and more predictive markers will be needed for metabolism-based treatments and personalized medicine.

Intralipid in Mitochondria

We recently demonstrated that the heart of late pregnant.LP) rodents is more prone to ischemia/reperfusion.I/R) injury compared to non-pregnant rodents. Lipids, particularly polyunsaturated fatty acids, have received special attention in the field of cardiovascular research. Here, we explored whether Intralipid.ITLD) protects the heart against I/R injury in LP rodents and investigated the mechanisms underlying this protection.

In-vivo female LP rat hearts or ex-vivo isolated Langendorff-perfused LP mouse hearts were subjected to ischemia followed by reperfusion with PBS or ITLD.one bolus of 5mg/kg of 20% in in-vivo and 1% in ex-vivo Myocardial infarct size, mitochondrial calcium retention capacity, genome-wide expression profiling, pharmacological inhibition and co-immunoprecipitation were performed. One bolus of ITLD at reperfusion significantly reduced the in-vivo myocardial infarct size in LP rats.23.3±2% vs. 55.5±3.4% in CTRL, p<0.01 Postischemic administration of ITLD also protected the LP hearts against I/R injury ex-vivo. ITLD significantly increased the threshold for the opening of the mitochondrial permeability transition pore in response to calcium overload.nmol-calcium/mg-mitochondrial protein: 290±17 vs. 167±10 in CTRL, p<0.01) and significantly increased phosphorylation of STAT3.1.8±0.08 vs. 1±0.16 in CTRL, p<0.05) and GSK-3β.2.63±0.55 vs. 1±0.0.34 in CTRL, p<0.05 The ITLD-induced cardioprotection was fully abolished by Stattic, a specific inhibitor of STAT3. Transcriptome analysis revealed caveolin 2.Cav2) was significantly upregulated by ITLD in hearts of LP rats under I/R injury. Co-immunoprecipitation experiments showed that Cav2 interacts with STAT3.

ITLD protects the heart in late pregnancy against I/R injury by inhibiting the mPTP opening through Cav2/STAT3/GSK-3β pathway.

Multiple studies have shown the effects of long-term exposure to high-fat or western diets on the vascular system. There is limited knowledge on the acute effects of high circulating fat levels, specifically on platelets, which have a role in many processes, including thrombosis and inflammation. This study investigated the effects of acute, high-fat exposure on platelet function and transcript profile. Twenty healthy participants were given an intravenous infusion of 20% Intralipid emulsion and heparin over 6 hours. Blood samples were taken prior to and the day after infusion to measure platelet function and transcript expression levels. Platelet aggregation was not significantly affected by Intralipid infusion, but, when mitochondria function was inhibited by carbonyl cyanide 3-chlorophenylhydrazone.CCCP) or oligomycin, platelet aggregation was higher in the post-infusion state compared to baseline. Through RNA sequencing, and verified by RT-qPCR, 902 miRNAs and 617 mRNAs were affected by Intralipid infusion. MicroRNAs increased include miR-4259 and miR-346, while miR-517b and miR-517c are both decreased. Pathway analysis identified two clusters significantly enriched, including cell motility. In conclusion, acute exposure to high fat affects mitochondrial-dependent platelet function, as well as the transcript profile.

Local anesthetic toxicity is thought to be mediated partly by inhibition of cardiac mitochondrial function. Intravenous.i.v.) lipid emulsion may overcome this energy depletion, but doses larger than currently recommended may be needed for rescue effect. In this randomized study with anesthetized pigs, we compared the effect of a large dose, 4 mL/kg, of i.v. 20% Intralipid®. n = 7) with Ringer's acetate. n = 6) on cardiovascular recovery after a cardiotoxic dose of bupivacaine. We also examined mitochondrial respiratory function in myocardial cell homogenates analyzed promptly after needle biopsies from the animals. Bupivacaine plasma concentrations were quantified from plasma samples. Arterial blood pressure recovered faster and systemic vascular resistance rose more rapidly after Intralipid than Ringer's acetate administration. p < 0.0001), but Intralipid did not increase cardiac index or left ventricular ejection fraction. The lipid-based mitochondrial respiration was stimulated by approximately 30% after Intralipid. p < 0.05) but unaffected by Ringer's acetate. The mean.standard deviation) area under the concentration-time curve.AUC) of total bupivacaine was greater after Intralipid.105.2.13.6) mg·min/L) than after Ringer's acetate.88.1.7.1) mg·min/L p = 0.019 After Intralipid, the AUC of the lipid-un-entrapped bupivacaine portion.97.0.14.5) mg·min/L) was 8% lower than that of total bupivacaine. p < 0.0001 To conclude, 4 mL/kg of Intralipid expedited cardiovascular recovery from bupivacaine cardiotoxicity mainly by increasing systemic vascular resistance. The increased myocardial mitochondrial respiration and bupivacaine entrapment after Intralipid did not improve cardiac function.

The clinically used lipid emulsion Intralipid.ILE) reduces ischemia reperfusion injury in healthy rodent hearts. We tested whether ILE is cardioprotective in postinfarct remodeled hearts. Post-infarct remodeled and sham Sprague-Dawley rat hearts were perfused in working mode and subjected to ischemia.15 minutes) and reperfusion.30 minutes Left ventricular.LV) work was measured in hearts that were untreated or that received ILE.1%) postconditioning administered at the onset of reperfusion, or the reactive oxygen species.ROS) scavenger N-(2-mercaptopropionyl)-glycine.10 μM) alone or in combination with ILE. Mitochondrial O2 consumption was measured in LV muscle fibers. Acetyl CoA production was calculated from the oxidation of [U-14C]glucose and [9,10-3H]palmitate. ROS production was assessed by loss of aconitase activity as well as by release of hydrogen peroxide. Phosphorylation of Akt, Erk1/2, and STAT3 were used to evaluate protection signaling. Remodeled hearts exhibited LV dysfunction and signs of hypertrophy consistent with significant postinfarct remodeling. ILE postconditioning enhanced the recovery of postischemic LV function in remodeled hearts, preserved energy metabolism in mitochondria, accelerated palmitate oxidation and acetyl CoA production, and activated Akt/Erk/STAT3 in a ROS-dependent manner. Protection by ILE postconditioning evolved rapidly within the first minutes of reperfusion without evidence of additional cardiotonic effects due to provision of supplementary energy substrates potentially released from ILE during reperfusion. ILE represents a novel and clinically feasible cardioprotective strategy that is highly effective in remodeled hearts. Our data provide a rationale for the clinical evaluation of ILE postconditioning where ILE is administered as a bolus at the onset of reperfusion.

Intralipid® administration at reperfusion elicits protection against myocardial ischemia-reperfusion injury. However, the underlying mechanisms are not fully understood.

Sprague-Dawley rat hearts were exposed to 15 min of ischemia and 30 min of reperfusion in the absence or presence of Intralipid® 1% administered at the onset of reperfusion. In separate experiments, the reactive oxygen species.ROS) scavenger N-(2-mercaptopropionyl)-glycine was added either alone or with Intralipid®. Left ventricular work and activation of Akt, STAT3, and ERK1/2 were used to evaluate cardioprotection. ROS production was assessed by measuring the loss of aconitase activity and the release of hydrogen peroxide using Amplex Red. Electron transport chain complex activities and proton leak were measured by high-resolution respirometry in permeabilized cardiac fibers. Titration experiments using the fatty acid intermediates of Intralipid® palmitoyl-, oleoyl- and linoleoylcarnitine served to determine concentration-dependent inhibition of complex IV activity and mitochondrial ROS release.

Intralipid® enhanced postischemic recovery and activated Akt and Erk1/2, effects that were abolished by the ROS scavenger N-(2-mercaptopropionyl)glycine. Palmitoylcarnitine and linoleoylcarnitine, but not oleoylcarnitine concentration-dependently inhibited complex IV. Only palmitoylcarnitine reached high tissue concentrations during early reperfusion and generated significant ROS by complex IV inhibition. Palmitoylcarnitine.1 µM), administered at reperfusion, also fully mimicked Intralipid®-mediated protection in an N-(2-mercaptopropionyl)-glycine -dependent manner.

Our data describe a new mechanism of postconditioning cardioprotection by the clinically available fat emulsion, Intralipid®. Protection is elicited by the fatty acid intermediate palmitoylcarnitine, and involves inhibition of complex IV, an increase in ROS production and activation of the RISK pathway.

To explore the effect of long-time propofol infusion on myocardial enzymes, mitochondrial cytochrome C and ATP in rabbits.

A total of 18 New Zealand rabbits were randomly divided into 3 groups: a control group, a propofol group and an intralipid group. The rabbits were continuously infused with 0.9% normal saline in the control group, 1% propofol in the propofol group, and 10% intralipid in the intralipidgroup, respectivey. The arterial blood was collected at 0, 8, 16 h and the end of experiment to examine creatine kinase.CK) and creatine kinase isoenzyme.CK-MB In the end, the myocardial mitochondria from myocardial tissues was separated by differential centrifugation, and mitochondrial cytochrome C content and adenosine triphosphate.ATP) levels were examined by high performance liquid chromatography.

Compared with the control group, the release of cytochrome C from mitochondria were increased in the propofol group and the intralipid group.both P<0.05), but there was no significant difference between them.P>0.05 There was also no significant difference in the ATP content of the mitochondria among the 3 groups.P>0.05 The levels of CK were increased at 8, 16 and 24 h after infusion in the propofol group and the intralipid group compared with that before the infusion.all P<0.05); compared with the control group, the levels of CK were increased at 8, 16 and 24 h after infusion in the propofol group and the intralipid group.all P<0.05); compared with the intralipid group, the levels of CK were increased at 8, 16 and 24 h after infusion in the propofol group.all P>0.05); compared with the control group, the levels of CK-MB were obviously increased in the infusion of propofol for 24 h in the propofol group.P<0.05

The levels of serum CK increase after the infusion of propofol and intralipid for a long time, and the levels of CK-MB also elevate in the infusion of propofol. Propofol and intralipid can increase the release of myocardial mitochondrial cytochrome C, but they don't affect the ATP production in myocardial mitochondrial.

We have recently shown that postischemic administration of intralipid protects the heart against ischemia-reperfusion injury. Here we compared the cardioprotective effects of intralipid with cyclosporine-A, a potent inhibitor of the mitochondrial permeability transition pore opening.

In vivo rat hearts or isolated Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion with intralipid.0.5%, 1% and 2% ex-vivo, and 20% in vivo), cyclosporine-A.0.2 μM, 0.8 μM, and 1.5 μM ex- vivo and 10 mg/kg in vivo), or vehicle. The hemodynamic function, infarct size, calcium retention capacity, mitochondrial superoxide production, and phosphorylation levels of protein kinase B.Akt)/glycogen synthase kinase-3β.GSK-3β) were measured. The values are mean ± SEM.

Administration of intralipid at reperfusion significantly reduced myocardial infarct size compared with cyclosporine-A in vivo.infarct size/area at risk)%: 22.9 ± 2.5% vs. 35.2 ± 3.5%; P = 0.030, n = 7/group Postischemic administration of intralipid at its optimal dose.1%) was more effective than cyclosporine-A.0.8 μM) in protecting the ex vivo heart against ischemia-reperfusion injury, as the rate pressure product at the end of reperfusion was significantly higher.mmHg · beats/min: 12,740 ± 675 [n = 7] vs. 9,203 ± 10,781 [n = 5], P = 0.024), and the infarct size was markedly smaller.17.3 ± 2.9 [n = 7] vs. 29.2 ± 2.7 [n = 5], P = 0.014 Intralipid was as efficient as cyclosporine-A in inhibiting the mitochondrial permeability transition pore opening.calcium retention capacity = 280 ± 8.2 vs. 260.3 ± 2.9 nmol/mg mitochondriaprotein in cyclosporine-A, P = 0.454, n = 6) and in reducing cardiac mitochondrial superoxide production. Unlike intralipid, which increased phosphorylation of Akt.6-fold) and GSK-3β.5-fold), cyclosporine-A had no effect on the activation of these prosurvival kinases.

Although intralipid inhibits the opening of the mitochondrial permeability transition pore as efficiently as cyclosporine-A, intralipid is more effective in reducing the infarct size and improving the cardiac functional recovery.

This study investigated whether caridoplegia solution with Emulsified Isoflurane.EI) could improve cardiaoprotection in a dog CPB model of great similarity to clinical settings. Adult dogs were randomly assigned to receive one of the following cardioplegia solutions: St. Thomas with EI.group ST+EI), St. Thomas with 30% Intralipid.group ST+EL) and St. Thomas alone.group ST The aorta was cross-clamped for two hours followed by reperfusion for another two hours, during which cardiac output was measured and dosages of positive inotropic agent to maintain normal hemodynamics were recorded. Serum level of cardiac troponin I.cTnI) and CK-MB were measured. Deletion of cardiac mitochondrial DNA was examined at the end of reperfusion. Compared with ST, ST+EI decreased the requirement of dopamine support while animals receiving ST+EI had a significantly larger cardiac output. ST+EI reduced post-CPB release of cTnI and CK-MB. Mitochondrial DNA loss was observed in only one of the tested animals from group ST+EI while it was seen in all the tested animals from group ST+EL and ST. Addition of emulsified isoflurane into cardioplegia solution protects against myocardial ischemia reperfusion injury. This protective effect might be mediated by preserving mitochondrial ultrastructure and DNA integrity.

Intralipid and Propofol

Propofol is an intravenous anesthetic that is used for procedural sedation, during monitored anesthesia care, or as an induction agent for general anesthesia. It may be administered as a bolus or an infusion or some combination of the two. Propofol is prepared in a lipid emulsion which gives it the characteristic milky white appearance. The formula contains soybean oil, glycerol, egg lecithin and a small amount of the preservative EDTA. Strict aseptic technique must be used when drawing up propofol as the emulsion can support microbial growth.

Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is an effective treatment for coronary artery and aortic valve diseases. However, the myocardium sustains reperfusion injury after ischemic cardioplegic arrest. Our objective was to assess the benefits of supplementing cardioplegia solution with the general anesthetic propofol in patients undergoing either coronary artery bypass grafting.CABG) or aortic valve replacement.AVR

A single-center, double-blind randomized controlled trial was carried out to compare cardioplegia solution supplemented with propofol.concentration 6 μg/mL) versus intralipid.placebo The primary outcome was cardiac troponin T release over the first 48 hours after surgery.

We recruited 101 participants.51 in the propofol group, 50 in the intralipid group); 61 underwent CABG and 40 underwent AVR. All participants were followed to 3 months. Cardiac troponin T release was on average 15% lower with propofol supplementation.geometric mean ratio, 0.85; 95% confidence interval [CI], 0.73-1.01; P = .051 There were no differences for CABG participants but propofol-supplemented participants undergoing AVR had poorer postoperative renal function.geometric mean ratio, 1.071; 95% CI, 1.019-1.125; P = .007), with a trend toward longer intensive care stay.median, 89.5 vs 47.0 hours; hazard ratio, 0.58; 95% CI, 0.31-1.09; P = .09) and fewer with perfect health.based on the EQ-5D health utility index) at 3 months.odds ratio, 0.26; 95% CI, 0.06-1.05; P = .058) compared with the intralipid group. Safety profiles were similar. There were no deaths.

Propofol supplementation in cardioplegia appears to be cardioprotective. Its influence on early clinical outcomes may differ between CABG and AVR surgery. A larger, multicenter study is needed to confirm or refute these suggestions.

The growing worldwide prevalence of food allergies is drawing attention to the risk of allergenic proteins found in intravenous medicinal products, particularly anaesthetics. Propofol induced anaphylaxis has been described. The presence of soybean oil and egg lecithins in the lipid emulsion highlights their suspected responsibility in certain cases. We report a case of anaphylaxis to propofol in an adult patient without food allergy to soy, but with a latent sensitization to soy. An IgE-dependent allergy to propofol was established by a basophil activation test. Here, we document for the first time the existence of specific IgEs to a 65kDa protein, found in soybean oil and soy flour. In the absence of data on the reactogenic threshold for allergenic food proteins injected intravenously, a risk appears to be established and leads us to recommend a systematic detection for proteins in the refined soybean oil used in the pharmaceutical industry for intravenous products.

To investigate the effects of different doses of propofol on pulmonary metastasis of intravenous injected tumor cells and expression of MTA1 and Wnt1 in the metastatic tumor in rats.

Forty male Fischer344 rats were randomly divided into 4 equal groups for intravenous administration of normal saline, intralipid, or propofol at the dose of 30 or 50 mg/kg pumped via the femoral vein. One hour after the infusion, MADB106 tumor cells.2×10) were injected intravenously in the rats. Pulmonary metastasis of the tumor cells was observed and the expression of MTA1 and Wnt1 in the metastatic tumor detected by immunohistochemistry 3 weeks later.

The rats receiving saline and intralipid treatments showed a comparable number of pulmonary metastasis and similar expression levels of MTA1 and Wnt1 in the metastatic tumor.P>0.05); the tumor number and MTA1 and Wnt1 were significantly lower in the two propofolgroups.P<0.01 The doses of propofol was inversely correlated with the number of pulmonary metastasis.r=-0.879) and expressions of MTA1.r=-0.980) and Wnt1.r=-0.916P<0.01), and MTA1 and Wnt1 expression levels in the metastatic tumors were closed correlated.r=0.902, P<0.01

Propofol can dose-dependently suppress pulmonary metastasis of intravenously injected tumor cells and down-regulate MTA1 and Wnt1 expressions in the metastatic tumor tissue.

Propofol is the most widely accepted intravenous anesthetic available for clinical use. However, neurotoxicity of propofol in the developing brain has been reported. This study investigated the effects of propofol on cognitive function in normal healthy adult mice. Thirty-three GFP-LC3 adult mice were included. Propofol was injected for anesthesia.n = 22 The sham control.n = 11) received intralipid injections. The mice completed a Y-maze test on 3 and 7 days after being anesthetized. Western blotting, immunofluorescence staining, and transmission electron microscopic.TEM) analyses were performed with their hippocampi. In addition, we conducted a separate ex vivo experiment using organotypic hippocampal slice cultures.OHSCs) to investigate the effects of propofol on induced autophagy. There was a significantly lower percentage of alternation in the Y-maze test on day 3 after propofol anesthesia than the control, but no difference was observed on day 7. Western blot analyses and immunofluorescence assays showed that the levels of cognitive function-related proteins significantly decreased in the propofol group compared to the control on day 3 but had recovered by day 7. In terms of autophagy-related proteins, western blot analyses and immunofluorescence assays showed that propofol increased autophagic induction, flux, and degradation of autophagosomes. Ex vivo experiments showed that propofol enhanced autophagic flux of the induced autophagy. In conclusion, although transient cognitive dysfunction occurred, adult mice recovered their cognitive function after the administration of propofol anesthesia. And this finding may be associated with enhanced autophagic flux.

The commercial propofol preparation in an intralipid solution causes marked vasodilatation. Both propofol and its solvent seem to stimulate the nitric oxide.NO) pathway. The role of intralipid in cardiac and regional haemodynamic changes induced by propofol and their respective interactions with the NO pathway was assessed.

Dogs were instrumented to record arterial pressure, heart rate, cardiac output, dP/dt.the first derivative of left ventricular pressure) and vertebral, carotid, coronary, mesenteric, hepatic, portal and renal blood flows. Experimental groups were as follows. Group 1.control; n = 11): N-methyl-L-arginine.L-NMA) 20 mg kg-1 i.v.; Group 2.n = 8): propofol.10 mg ml-1) 4 mg kg-1 i.v. bolus followed by 0.6 mg kg-1 min-1; Group 3.n = 6): intralipid 0.25 ml kg-1 bolus followed by 0.06 ml kg-1 min-1. After 60 min, L-NMA was injected in Groups 2 and 3.

Propofol induced increases in heart rate, coronary and carotid blood flows, and decreases in systemic vascular resistance and dP/dt. Intralipid increased renal blood flow, carotid vascular resistance and mesenteric vascular resistance. In the presence of intralipid, L-NMA-induced pressor response and systemic, carotid and renal vasoconstriction were more pronounced than in control dogs.

Except for the coronary and carotid circulations, intralipid modulates the NO pathway in cardiac and regional blood flow.

John B. Glen, a British veterinarian and researcher at ICI.Imperial Chemical Industries ) spent 13 years developing propofol, an effort which led to the awarding to him of the prestigious 2018 Lasker award for clinical research. Propofol was originally developed as ICI 35868.

Clinical trials followed in 1977, using a form solubilised in cremophor EL. However, due to anaphylactic reactions to cremophor, this formulation was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil/propofol mixture in water. The emulsified formulation was relaunched in 1986 by ICI.now AstraZeneca) under the brand name Diprivan. The currently available preparation is 1% propofol, 10% soybean oil, and 1.2% purified egg phospholipid as an emulsifier, with 2.25% glycerol as a tonicity-adjusting agent, and sodium hydroxide to adjust the pH. Diprivan contains EDTA, a common chelation agent, that also acts alone.bacteriostatically against some bacteria) and synergistically with some other antimicrobial agents. Newer generic formulations contain sodium metabisulfite or benzyl alcohol as antimicrobial agents. Propofol emulsion is a highly opaque white fluid due to the scattering of light from the tiny.about 150-nm) oil droplets it contains.

Intravenous lipid emulsions have been used experimentally since at least the 19th century. An early product marketed in 1957 under the name Lipomul was briefly used in the United States but was subsequently withdrawn due to side effects. Intralipid was invented by the Swedish physician and nutrition researcher Arvid Wretlind, and was approved for clinical use in Sweden in 1962. In the United States, the Food and Drug Administration initially declined to approve the product due to prior experience with another fat emulsion. It was approved in the United States in 1972.

INTRALIPID® 20%.A 20% INTRAVENOUS FAT EMULSION) IS A STERILE, NON-PYROGENIC FAT EMULSION PREPARED FOR INTRAVENOUS ADMINISTRATION AS A SOURCE OF CALORIES AND ESSENTIAL FATTY ACIDS. IT IS MADE UP OF 20% SOYBEAN OIL, 1.2% EGG YOLK PHOSPHOLIPIDS, 2.25% GLYCERIN, AND WATER FOR INJECTION. IN ADDITION, SODIUM HYDROXIDE HAS BEEN ADDED TO ADJUST THE PH SO THAT THE FINAL PRODUCT PH IS 8. PH RANGE IS 6 TO 8.9. The major component fatty acids are linoleic.44-62%), oleic.19-30%), palmitic.7-14%), linolenic.4- 11%) and stearic.1.4-5.5%

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