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

A panel of clinically used tyrosine kinase inhibitors were 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.

► Nilotinib compared to panel of tyrosine kinase inhibitors most potently reverse ABCB1, ABCG2 and ABCC10 transporters mediated drug resistance. ► Nilotinib blocks ABCB1, ABCG2 and ABCC10 mediated multi-drug resistance in mouse xenograft models. ► Nilotinib enhanced the antitumor response of paclitaxel in the ABCB1- and ABCC10-xenograft, and doxorubicin in a ABCG2-xenograft model. ► Nilotinib warrant consideration as viable combinations in the clinic with agents that suffer from MDR-mediated insensitivity.