Wu Chung-Pu, Hsiao Sung-Han, Murakami Megumi, Lu Ming-Jie, Li Yan-Qing, Hsieh Chia-Hung, Ambudkar Suresh V, Wu Yu-Shan
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Neurosurgery, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Cancer Lett. 2017 Nov 28;409:56-65. doi: 10.1016/j.canlet.2017.08.035. Epub 2017 Sep 8.
The multidrug resistance (MDR) phenotype associated with the overexpression of ATP-binding cassette (ABC) drug transporters ABCB1, ABCC1 and ABCG2 is a major obstacle in cancer chemotherapy. Numerous epidermal growth factor receptor (EGFR) inhibitors have previously been shown capable of reversing MDR in ABCG2-overexpressing cancer cells. However, most of them are not transporter-specific due to the substantial overlapping substrate specificity among the transporters. In this study, we investigated the interaction between ABCG2 and tyrphostin RG14620, an EGFR inhibitor of the tyrphostin family, in multidrug-resistant cancer cell lines. We found that at nontoxic concentrations, tyrphostin RG14620 enhances drug-induced apoptosis and restores chemosensitivity to ABCG2-overexpressing multidrug-resistant cancer cells. More importantly, tyrphostin RG14620 is selective to ABCG2 relative to ABCB1 and ABCC1. Our findings were further supported by biochemical assays demonstrating that tyrphostin RG14620 stimulates ATP hydrolysis and inhibits photoaffinity labeling of ABCG2 with IAAP, and by a docking analysis of tyrphostin RG14620 in the drug-binding pocket of this transporter. Taken together, our findings indicate that tyrphostin RG14620 is a potent and selective modulator of ABCG2 that may be useful to overcome chemoresistance in patients with drug-resistant tumors.
与ATP结合盒（ABC）药物转运蛋白ABCB1、ABCC1和ABCG2过表达相关的多药耐药（MDR）表型是癌症化疗中的主要障碍。此前已表明，许多表皮生长因子受体（EGFR）抑制剂能够逆转ABCG2过表达癌细胞中的MDR。然而，由于这些转运蛋白之间存在大量重叠的底物特异性，它们中的大多数并非转运蛋白特异性的。在本研究中，我们在多药耐药癌细胞系中研究了ABCG2与酪氨酸磷酸化抑制剂RG14620（酪氨酸磷酸化抑制剂家族的一种EGFR抑制剂）之间的相互作用。我们发现，在无毒浓度下，酪氨酸磷酸化抑制剂RG14620可增强药物诱导的细胞凋亡，并恢复对ABCG2过表达的多药耐药癌细胞的化学敏感性。更重要的是，相对于ABCB1和ABCC1，酪氨酸磷酸化抑制剂RG14620对ABCG2具有选择性。生化分析表明酪氨酸磷酸化抑制剂RG14620刺激ATP水解并抑制ABCG2与IAAP的光亲和标记，以及对酪氨酸磷酸化抑制剂RG14620在该转运蛋白药物结合口袋中的对接分析进一步支持了我们的发现。综上所述，我们的发现表明酪氨酸磷酸化抑制剂RG14620是一种有效的ABCG2选择性调节剂，可能有助于克服耐药肿瘤患者的化疗耐药性。
