PI۳K/Akt inhibition and down-regulation of BCRP re-sensitize MCF۷ breast cancer cell line to mitoxantrone chemotherapy

Objective(s):Multidrug resistance (MDR) of cancer cells is a major obstacle to successful chemotherapy. Overexpression of breast cancer resistance protein (BCRP) is one of the major causes of MDR. In addition, it has been shown that PI۳K/Akt signaling pathway involves in drug resistance. Therefore, we evaluated the effects of novel approaches including siRNA directed against BCRP and targeted therapy against PI۳K/Akt signaling pathway using LY۲۹۴۰۰۲ (LY) to re-sensitize breast cancer MCF۷ cell line to mitoxantrone (MTX) chemotherapy. Materials and Methods: Anticancer effects of MTX, siRNA, and LY alone and in combination were evaluated in MCF۷ cells using MTT cytotoxicity assay and flow cytometry analysis of cell cycle distribution and apoptosis induction. Results: MTT and apoptosis assays showed that both MTX and LY inhibited cell proliferation and induced apoptosis in MCF۷ cells. Results indicated that inhibition of BCRP by siRNA or PI۳K/Akt signaling pathway by LY significantly increased sensitivity of MCF۷ cells to antiproliferation and apoptosis induction of MTX. Furthermore, MTX showed G۲/M arrest, whereas LY induced G۰/G۱ arrest in cell cycle distribution of MCF۷ cells. Combination of siRNA or LY with MTX chemotherapy significantly increased accumulation of MCF۷ cells in the G۲/M phase of cell cycle. Conclusion: Combination of MTX chemotherapy with BCRP siRNA and PI۳K/Akt inhibition can overcome MDR in breast cancer cells. This study furthermore suggests that novel therapeutic approaches are needed to enhance anticancer effects of available drugs in breast cancer

Keywords:

Breast Cancer , BCRP , Combination therapy , Mitoxantrone , PI۳K/Akt , siRNA