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Abstract
BackgroundHigh mortality rates in ovarian cancer are largely a result of resistance to currently used chemotherapies. Expanding therapies with a variety of drugs has the potential to reduce this high mortality rate. Metformin and phenethyl isothiocyanate (PEITC) are both potentially useful in ovarian cancer, and they are particularly attractive because of their safety.MethodsCell proliferation of each drug and drug combination was evaluated by hemacytometry with Trypan blue exclusion or Sytox green staining for cell death. Levels of total and cleaved PARP were measured by Western blot. General cellular and mitochondrial reactive oxygen species were measured by flow cytometry and live cell confocal microscopy with the fluorescent dyes dihydroethidine and MitoSOX.ResultsIndividually, metformin and PEITC each show inhibition of cell growth in multiple ovarian cancer cell lines. Alone, PEITC was also able to induce apoptosis, whereas metformin was primarily growth inhibitory. Both total cellular and mitochondrial reactive oxygen species were increased when treated with either metformin or PEITC. The growth inhibitory effects of metformin were reversed by methyl succinate supplementation, suggesting complex I plays a role in metformin's anti-cancer mechanism. PEITC's anti-cancer effect was reversed by N-acetyl-cysteine supplementation, suggesting PEITC relies on reactive oxygen species generation to induce apoptosis. Metformin and PEITC together showed a synergistic effect on ovarian cancer cell lines, including the cisplatin resistant A2780cis.ConclusionsHere we show that when used in combination, these drugs are effective in both slowing cancer cell growth and killing ovarian cancer cells in vitro. Furthermore, the combination of these drugs remains effective in cisplatin resistant cell lines. Novel combinations such as metformin and PEITC show promise in expanding ovarian cancer therapies and overcoming the high incidence of cisplatin resistant cancers.
Highlights
High mortality rates in ovarian cancer are largely a result of resistance to currently used chemotherapies
phenethyl isothiocyanate (PEITC) is cytotoxic in multiple ovarian cancer lines Across many human epithelial ovarian cancer cell lines, metformin was found to significantly lower cell proliferation (Figure 1A)
These results suggest that previously identified mechanisms of Electron transport chain (ETC) complex inhibition by both metformin and PEITC results in an increase of reactive oxygen species (ROS) within the cancer cell
Summary
High mortality rates in ovarian cancer are largely a result of resistance to currently used chemotherapies. Expanding therapies with a variety of drugs has the potential to reduce this high mortality rate. Ovarian cancer continues to have a disturbing discrepancy in incidence to mortality rate. The difference in incidence to mortality rates is a combined result of poor ovarian cancer screening and rapid development of resistance to current chemotherapeutics. Expanding available chemotherapies may improve the long term survival of ovarian cancer patients by overcoming the resistance to platinum based therapies and providing alternate mechanisms for cancer cell death. Metformin and PEITC have both been individually identified as potential ovarian cancer therapies [2,3,4,5]. This work examines the combination of metformin and PEITC as a novel treatment combination
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