Long term treatment of metformin impedes development of chemoresistance by regulating cancer stem cell differentiation through taurine generation in ovarian cancer cells.

Abstract

Development of resistance poses a significant challenge to effective first-line platinum based therapy for epithelial ovarian cancer patients. Cancer Stem Cells are envisaged as a critical underlying factor for therapy resistance. Thus, there is a critical need for developing approaches to diminish the enrichment of cancer stem cells and acquirement of resistance. Administration of metformin, a commonly prescribed drug against Type II diabetes exhibited promising effect in the management of ovarian cancer. However, the effect of long term administration of low dose of metformin as an adjuvant to cisplatin and paclitaxel during acquirement of chemoresistant phenotype has not been investigated so far. Using two isogenic cellular chemoresistant models (A2780 and OAW42) developed in the presence or absence of metformin, we demonstrated the ability of metformin to impede the development of resistance through increased drug sensitivity, increased proliferation, and reduced migratory abilities of the resistant cells. Metformin introduction also decreased the cancer stem cell population, expression of specific biomarkers and pluripotent genes. Further metabolic profiling of these cells using 1H-Nuclear Magnetic Resonance spectroscopy revealed significant modulation in taurine and histidine levels in resistant cells developed in the presence of metformin. Intriguingly, taurine treatment considerably reduced the cancer stem cell population and chemoresistance in resistant cells, indicating a novel role of taurine in differentiation of ovarian cancer stem cells. Altogether this is the first report on the potential role of metformin for targeting the cancer stem cell population via up regulation of taurine, leading to impediment in the acquirement of chemoresistance.