Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter.
Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter.
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Trametinib 通过靶向 ABCB1 转运蛋白来调节癌症多药耐药性。
DOI：
10.18632/oncotarget.3820
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发表时间：
2015-06-20
期刊：
影响因子：
--
通讯作者：
Shi Z
中科院分区：
文献类型：
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作者：
Qiu JG;Zhang YJ;Li Y;Zhao JM;Zhang WJ;Jiang QW;Mei XL;Xue YQ;Qin WM;Yang Y;Zheng DW;Chen Y;Wei MN;Shi Z
三磷酸腺苷（ATP）结合盒（ABC）转运蛋白的过度表达是肿瘤细胞产生多药耐药（MDR）的主要原因之一。曲美替尼是一种新型特异性小分子丝裂原活化细胞外信号调节激酶（MEK）抑制剂，目前临床上用于治疗黑色素瘤。在这项研究中，我们研究了曲美替尼对ABC转运蛋白介导的MDR的影响。曲美替尼显著增强了两种ABCB 1底物长春新碱和多柔比星对过表达ABCB 1的癌细胞生长抑制、细胞周期阻滞和诱导凋亡的作用，但对ABCC 1和ABCG 2无影响。此外，曲美替尼没有改变非ABCB 1底物顺铂的敏感性。从机制上讲，曲美替尼有效阻断ABCB 1的药物外排活性，增加罗丹明123和多柔比星的细胞内蓄积，并刺激ABCB 1的ATP酶，而不改变ABCB 1的表达。重要的是，曲美替尼显著增强了长春新碱对ABCB 1过表达癌细胞裸鼠移植瘤的作用。预测的结合模式显示了曲美替尼在ABCB 1的大药物结合空腔内的疏水相互作用。因此，我们的研究结果可能对曲美替尼在联合治疗癌症中的应用具有重要意义。
Overexpression of adenine triphosphate (ATP)-binding cassette (ABC) transporters is one of the main reasons of multidrug resistance (MDR) in cancer cells. Trametinib, a novel specific small-molecule mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, is currently used for the treatment of melanoma in clinic. In this study, we investigated the effect of trametinib on MDR mediated by ABC transporters. Trametinib significantly potentiated the effects of two ABCB1 substrates vincristine and doxorubicin on inhibition of growth, arrest of cell cycle and induction of apoptosis in cancer cells overexpressed ABCB1, but not ABCC1 and ABCG2. Furthermore, trametinib did not alter the sensitivity of non-ABCB1 substrate cisplatin. Mechanistically, trametinib potently blocked the drug-efflux activity of ABCB1 to increase the intracellular accumulation of rhodamine 123 and doxorubicin and stimulates the ATPase of ABCB1 without alteration of the expression of ABCB1. Importantly, trametinib remarkably enhanced the effect of vincristine against the xenografts of ABCB1-overexpressing cancer cells in nude mice. The predicted binding mode showed the hydrophobic interactions of trametinib within the large drug binding cavity of ABCB1. Consequently, our findings may have important implications for use of trametinib in combination therapy for cancer treatment.