Nilotinib potentiates anticancer drug sensitivity in murine ABCB1- ABCG2- and ABCC10-multidrug resistance xenograft models

摘要

A panel of clinically used tyrosine kinase inhibitors was compared and nilotinib was found to most potently sensitize specific anticancer agents by blocking the functions of ABCB1/P-glycoprotein, ABCG2/BCRP and ABCC10/MRP7 transporters involved in multi-drug resistance. Nilotinib appreciably enhanced the antitumor response of 1) paclitaxel in the ABCB1- and novel ABCC10-xenograft models, and 2) doxorubicin in a novel ABCG2-xenograft model. With no apparent toxicity observed in the above models, nilotinib attenuated tumor growth synergistically and increased paclitaxel concentrations in ABCB1-overexpressing tumors. The beneficial actions of nilotinib warrant consideration as viable combinations in the clinic with agents that suffer from MDR-mediated insensitivity.