Abstract
The presence of acquired multidrug resistance (MDR) is one of the primary impediments to the success of chemotherapy. MDR is often a result of overexpression of ATP-binding cassette (ABC) transporters, which are involved in the extrusion of therapeutic drugs. Recently, it was shown that several ABC transporters could be modulated by specific tyrosine-kinase inhibitors (TKIs). Ponatinib, a multi-targeted TKI, inhibits the activity of BCR-ABL with very high potency and broad specificity, including the T315I mutation which confers resistance to other TKIs. It was reported that ponatinib was capable of reversing breast cancer resistance protein (BCRP)- and P-glycoprotein (P-gp)-mediated MDR. In the present study, we report for the first time that ponatinib also potentiates the cytotoxicity of widely used therapeutic substrates of MRP7, such as paclitaxel, docetaxel, vincristine and vinblastine. Ponatinib significantly enhances the accumulation of [3H]-paclitaxel in cells expressing MRP7. Furthermore, accumulation of [3H]-paclitaxel was achieved by inhibition of MRP7-mediated transport. Ponatinb limited drug export via MRP7 by multiple mechanisms. In addition to inhibition of pump function, ponatinib also downregulated MRP7 protein expression in a time- and concentration-dependent manner. Thus, ponatinib may represent a potential reversal agent for the treatment of MDR and may be useful for combination therapy in MDR cancer patients in clinical practice.