Tyrosine Kinase Inhibitors As Modulators of Multidrug Resistance in Cancer
Zhe-Sheng (Jason) Chen, Charles R. Ashby, Jr.
College of Pharmacy and Health Sciences, Department of Pharmaceutical Sciences
Abstract: Through an extensive screening, we have found that several tyrosine kinase inhibitors, erlotinib, lapatinib, AG1478 and nilotinib, potently reversed the multidrug resistance (MDR) in cancer cells that overexpressed ABCB1 or ABCG2. In our experiments, these compounds potentiated the cytotoxicity of several ABCB1 substrates including colchicine, vinblastine, and paclitaxel, and several ABCG2 substrates such as mitoxantrone and doxorubicin but not non-ABCB1/ABCG2 substrate cisplatin, and significantly reversed the MDR of cancer cells in a concentration-dependent manner. Furthermore, these compounds had no or very little effect on the response to cytotoxic agents in cells lacking ABCB1 or ABCG2 expression. Most of these compounds (IC50 > 20 µM) at 5~10 µM are not toxic to all the cell lines we used, regardless of their ABC drug transporter status. Accumulation and efflux studies with the ABCB1 substrate [3H]-paclitaxel or the ABCG2 substrate [3H]-mitoxantrone demonstrated that these compounds time-dependently increased the intracellular accumulation of [3H]-paclitaxel or [3H]-mitoxantrone by directly inhibiting ABCB1- or ABCG2-mediated drug efflux. In addition, treatment of cells up to 72 hours with these compounds did not alter the expression of ABCB1 or ABCG2. However, most of them efficaciously stimulated the activity of ATPase of ABCB1 and ABCG2 and inhibited the photolabeling of these transporters with the transport substrate [125I]-Iodoarylazidoprazosin indicating that these drugs interact at the drug-substrate site(s) rather than the ATP-binding sites. Importantly, lapatinib also strongly enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBv200 cell xenografts in nude mice. Overall, our results demonstrate that these drugs efficiently inhibit the function of ABCB1 and ABCG2 through direct interactions, and tyrosine kinase inhibitors are a new class of potential reversing agents for treatment of MDR in ABCB1 and/or ABCG2 overexpressing tumors.