Interaction of Tyrosine Kinase Inhibitors with the MDR-Related ABC Transporter Proteins

Xiao-Kun      Wang; Li-Wu      Fu

doi:10.2174/138920010792927316

Abstract

Tyrosine kinase inhibitors (TKIs) are a new class of highly-selective and molecularly targeted anticancer agents. Most of these newly developed TKIs are hydrophobic, thus allowing them to rapidly penetrate the cell membrane to reach their specific intracellular targets. However, their therapeutic potential could be significantly hindered by the overexpression of certain ATP binding cassette (ABC) membrane transporters, which extrude hydrophobic drugs and result in cellular resistance to TKIs by tumor cells. Moreover, it has been recently demonstrated that some TKIs could upregulate ABC transporters in tumor cells, thereby effectively reducing their intracellular accumulation and antitumor efficacy. On the other hand, other TKIs were found to interact with ABC transporters and reverse multi-drug resistance (MDR) of tumor cells. In this review, the interaction of several TKIs, currently in clinical use or being developed in clinical trials, with the MDR-related ABC transporters, in particular ABCB1, ABCC1 and ABCG2, will be discussed.

Keywords: ABC transporters, anticancer drug, interaction, multidrug resistance (MDR), overexpression, tyrosine kinase inhibitors (TKIs), reversal effect, Imatinib mesylate, chronic myelogenous leukemia, kinases c-Kit, platelet-derived growth factor receptor, eosinophilic leukemia, gastrointestinal stromal tumors, nilotinib, Dasatinib, Sunitinib, Lapatinib, Sorafenib, Gefitinib, Erlotinib, Pazopanib, transmembrane domains, TMDs, distinctive nucleotidebinding domains (NBDs), valspodar (PSC833), elacridar, GF120918, zosuquidar, LY335979, tariquidar, XR9576, laniquidar, R101933, ONT-093, vincristine, VCR, paclitaxel, etoposide, actinomycin D, ACD