Functional daidzein enhances the anticancer effect of topotecan and reverses BCRP-mediated drug resistance in breast cancer

Abstract

Topotecan (TPT), a semisynthetic derivative of camptothecin, has been used in cancer chemotherapy, but side effects and drug resistance limit its clinical application. Daidzein (DAI), a natural isoflavone and bioactive food component widely existing in fruits, nuts, soybeans and soy-based products, is a type of phytoestrogen. Combination treatment with DAI and TPT showed a strong synergistic effect on tumor cells, with a 0.10˜0.66 combined index, by increasing TPT inhibition on Topo Ⅰ, resulting in more cells arresting at the G2/M phase and inducing more cells to undergo apoptosis. In addition, the resistance of MCF7/ADR cells to TPT was reversed (the resistance index decreased from 7.17 to 0.77) by inhibiting the expression of ERα and BCRP to increase TPT accumulation intracellularly. Moreover, the combination of DAI and TPT showed a stronger inhibitory effect (P < 0.01) on tumor growth in both MCF7 and MCF7/ADR xenograft models than the 9 mg/kg TPT monotherapy group. Our results may provide a reasonable, new approach to develop safe and efficient nutrition components from foods for breast cancer combination treatment.