A Y1 receptor ligand synergized with a P-glycoprotein inhibitor improves the therapeutic efficacy of multidrug resistant breast cancer.

Abstract

Multidrug resistance (MDR) is one of the main reasons for the inefficiency of cancer chemotherapy. As a consequence of MDR, the expression level of membrane proteins might be changed, which can thus be used to develop a novel strategy for its treatment. Based on the high overexpression of Y1 receptor (Y1R) protein and P-glycoprotein (P-gp) in the multidrug resistant breast cancer cell line, a selective Y1R ligand [Asn6, Pro34]-NPY (AP) was employed to stabilize the chemotherapeutic drug doxorubicin (DOX) and P-gp inhibitor tariquidar (Tar) co-loaded nanomicelles at the physiological level. This also improved the targeted delivery of DOX and Tar into MCF-7/ADR cells. Co-delivered Tar further impedes the efflux of DOX and enhances its accumulation in the nuclei of drug resistant cancer cells, thereby inducing significant inhibition of cell growth. The synergistic effect of AP and Tar generates an excellent in vivo tumor targeting and antitumor efficacy of DOX with prolonged survival and minimized side effects, especially for liver metastasis. In general, Y1R as a novel target site and its selective ligand AP synergized with the P-gp inhibitor can be used for a more precise MDR breast cancer treatment.