Combination effect of doxorubicin and HIF inhibitor on MCF-7 CD44+/CD24- subpopulation cells in hypoxic condition

Abstract

Hypoxia-inducible factors (HIFs) and cancer stem cells (CSCs) are two challenging causes ofradiotherapy and chemotherapy resistance, leading to most cases of failure and recurrence in breastcancer therapy. This study was conducted to investigated the inhibitory effect of combinationtherapy with doxorubicin (an anthracycline) and FM19G11 (an HIF inhibitor) on MCF-7 cells andtheir CSC-like cells (CSC-LCs). MCF-7 CSC-LCs with a CD44+/CD24-phenotype were sorted andcharacterized by flow cytometry. A combination of doxorubicin and FM19G11 caused more cytotoxiceffects on MCF-7 and CSC-LCs compared to doxorubicin monotherapy. The largest synergistic effectwas observed in CSC-LCs under hypoxic conditions; however, MCF-7 cells showed no synergism innormoxic conditions. The administration of doxorubicin and FM19G11 induced late apoptotic andnecrotic cell death in MCF-7 and CSC-LCs. Additionally, G2 phase arrest was observed in bothcells. Our results demonstrated that co-administration of FM19G11 and doxorubicin had a synergisticeffect in hypoxia and improved drug resistance in breast cancer stem cells