Enhancing therapeutic efficacy in breast cancer: a study on the combined cytotoxic effects of doxorubicin and MPC-3100.

Abstract

Combination therapy is a strategy aimed at the combined use of agents targeting different mechanisms in cancer treatment. This study aimed to examine the cytotoxic and apoptotic effects of the traditional chemotherapeutic agent doxorubicin (DOX) and the next-generation HSP90 inhibitor MPC-3100 on breast cancer cell lines. Firstly, molecular docking analyses were performed, and then the MTT test was conducted to evaluate the individual and combined cytotoxic effects of DOX and MPC-3100 on MCF-7 and MDA-MB-231 breast cancer cell lines. The effect of two drugs combination was assessed by the Chou and Talalay approach. To further investigate the underlying molecular mechanism responsible for this synergistic effect, the gene expression levels of apoptotic and heat shock proteins (HSP), as well as the protein expression levels, were examined using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western Blotting, respectively. Based on the molecular docking results, it was observed that MPC-3100 specifically binds to the ATP binding pocket of Hsp90, exhibiting an estimated free binding energy of -7.9kcal/mol. MTT results indicated that both DOX and MPC-3100, as well as their combination, exhibited dose-dependent cytotoxicity. The drug combination showed a synergistic effect on both MCF-7 and MDA-MB-231 cell lines. Finally, the investigated molecular mechanism demonstrated that the combination of DOX and MPC-3100 induced apoptosis in breast cancer cells more efficiently than either drug alone. This study showed a possible coordinated mechanism of action between DOX and MPC-3100, pointing to the possibility of a more effective therapeutic strategy for breast cancer therapy.