TY - JOUR ID - 4410 TI - PI3K/Akt inhibition and down-regulation of BCRP re-sensitize MCF7 breast cancer cell line to mitoxantrone chemotherapy JO - Iranian Journal of Basic Medical Sciences JA - IJBMS LA - en SN - 2008-3866 AU - Komeili-Movahhed, Tahereh AU - Fouladdel, Shamileh AU - Barzegar, Elmira AU - Atashpour, Shekoufeh AU - Ghahremani, Mohammad Hossein AU - Ostad, Seyed Nasser AU - Madjd, Zahra AU - Azizi, Ebrahim AD - Molecular Research Laboratory, Department of Pharmacology and Toxicology, Tehran University of Medical Sciences, Tehran, Iran AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran AD - Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran Y1 - 2015 PY - 2015 VL - 18 IS - 5 SP - 472 EP - 477 KW - Breast Cancer KW - BCRP KW - Combination therapy KW - Mitoxantrone KW - PI3K/Akt KW - siRNA DO - 10.22038/ijbms.2015.4410 N2 - 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 PI3K/Akt signaling pathway involves in drug resistance. Therefore, we evaluated the effects of novel approaches including siRNA directed against BCRP and targeted therapy against PI3K/Akt signaling pathway using LY294002 (LY) to re-sensitize breast cancer MCF7 cell line to mitoxantrone (MTX) chemotherapy. Materials and Methods: Anticancer effects of MTX, siRNA, and LY alone and in combination were evaluated in MCF7 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 MCF7 cells. Results indicated that inhibition of BCRP by siRNA or PI3K/Akt signaling pathway by LY significantly increased sensitivity of MCF7 cells to antiproliferation and apoptosis induction of MTX. Furthermore, MTX showed G2/M arrest, whereas LY induced G0/G1 arrest in cell cycle distribution of MCF7 cells. Combination of siRNA or LY with MTX chemotherapy significantly increased accumulation of MCF7 cells in the G2/M phase of cell cycle. Conclusion: Combination of MTX chemotherapy with BCRP siRNA and PI3K/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 UR - https://ijbms.mums.ac.ir/article_4410.html L1 - https://ijbms.mums.ac.ir/article_4410_7e6d4a7a6fbb6fb16d249d55a5e3d5c6.pdf ER -