Zhang Hui, Zhang Yun-Kai, Wang Yi-Jun, Kathawala Rishil J, Patel Atish, Zhu Hua, Sodani Kamlesh, Talele Tanaji T, Ambudkar Suresh V, Chen Zhe-Sheng, Fu Li-Wu
Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA.
Cancer Sci. 2014 Aug;105(8):1071-8. doi: 10.1111/cas.12462. Epub 2014 Aug 21.
ATP-binding cassette (ABC) transmembrane proteins evidently decrease the intracellular accumulation of substrate chemotherapeutic drugs by extruding them against a concentration gradient, thereby inducing drug resistance. Here we reported the effect of WHI-P154, an irreversible inhibitor of Janus kinase 3 and epidermal growth factor receptor tyrosine kinases, on reversing ABC transporters-mediated drug resistance. We found that WHI-P154 significantly enhanced the sensitivity of ABCG2-overexpressing cells to its substrates. WHI-P154 moderately sensitized ABCB1-overexpressing KB-C2 cells to its substrates whereas showed no sensitizing effect on ABCC1-, ABCC2 or ABCC10-mediated drug resistance. Moreover, WHI-P154 produced a significant increase in the intracellular accumulation of [³H]-mitoxantrone in ABCG2-overexpressing cells. The expression levels nor the localization of the ABCG2 protein was altered after treatment of ABCG2-overexpressing cells with WHI-P154. Further studies indicated that WHI-P154 enhanced the ATPase activity of ABCG2 at low concentrations (<10 μM). Additionally, a docking model predicted the binding conformation of WHI-P154 within the transmembrane region of homology-modeled human ABCG2 transporter. Collectively, these findings highlighted WHI-P154 could significantly reverse ABCG2-mediated multidrug drug resistance by directly blocking the efflux function.
ATP结合盒（ABC）跨膜蛋白显然通过逆浓度梯度将底物化疗药物排出细胞，从而降低其在细胞内的蓄积，进而诱导耐药性。在此，我们报告了Janus激酶3和表皮生长因子受体酪氨酸激酶的不可逆抑制剂WHI-P154对逆转ABC转运蛋白介导的耐药性的作用。我们发现，WHI-P154显著增强了过表达ABCG2的细胞对其底物的敏感性。WHI-P154使过表达ABCB1的KB-C2细胞对其底物产生适度的敏感性，而对ABCC1、ABCC2或ABCC10介导的耐药性没有增敏作用。此外，WHI-P154使过表达ABCG2的细胞内[³H] - 米托蒽醌的蓄积显著增加。用WHI-P154处理过表达ABCG2的细胞后，ABCG2蛋白的表达水平和定位均未改变。进一步研究表明，低浓度（<10 μM）时，WHI-P154增强了ABCG2的ATP酶活性。此外，一个对接模型预测了WHI-P154在同源建模的人ABCG2转运蛋白跨膜区域内的结合构象。总的来说，这些发现突出表明WHI-P154可通过直接阻断外排功能显著逆转ABCG2介导的多药耐药性。
