Rutin Alleviates Breast Cancer Resistance to Tamoxifen By Downregulating ABC Transporters, Inducing ROS Generation and Resetting Redox Status

Breast cancer is one of the most lethal cancers in women worldwide. Tamoxifen (TAM), a nonsteroidal antiestrogen, is a highly successful treatment for breast cancer. However, developed resistance to TAM can substantially impair chemotherapy efficacy, resulting in poor prognosis and cancer recurrence. Rutin (RUT) is a dietary flavonoid with potent anticancer activities, however its fundamental mechanisms in the treatment of TAM-resistant breast cancer remain obscure. We used cell viability assay, qPCR, flow cytometric analysis combined with immunoblotting and molecular docking studies to assess the effects of RUT on chemoresistance, ATP-binding cassette transporters (ABC), and redox status resetting in TAM resistant breast cancer cells. Our results revealed that the treatment of resistant LCC2 cells with a combination of TAM and RUT effectively inhibited cell growth and proliferation. RUT reverses the resistance of LCC2 cells to TAM by downregulating the expression of ABCB1, ABCC1, ABCC2, and ABCG2 multidrug resistance genes and inducing the production of reactive oxygen species. Further, western blot results exhibited that TAM combined with RUT reduced the expression levels of Nrf2, GCL, GLS, and SLCA711 proteins in LCC2 cells, which was corroborated by molecular docking. TAM and RUT combination may provide a promising treatment pathway to conquer TAM resistance and hence extend the life expectancy in breast cancer patients.