Olmutinib (HM61713) reversed multidrug resistance by inhibiting the activity of ATP-binding cassette subfamily G member 2 in vitro and in vivo
Olmutinib (HM61713) reversed multidrug resistance by inhibiting the activity of ATP-binding cassette subfamily G member 2 in vitro and in vivo
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DOI：
10.1016/j.apsb.2018.06.002
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发表时间：
2018-06
期刊：
影响因子：
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通讯作者：
Zhi-qiang Zhang;Xiaoran Guo;K. To;Zhen Chen;Xiaona Fang;M. Luo;Chunling Ma;Jianhua Xu;Shirong Yan;Liwu Fu
中科院分区：
文献类型：
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作者：
Zhi-qiang Zhang;Xiaoran Guo;K. To;Zhen Chen;Xiaona Fang;M. Luo;Chunling Ma;Jianhua Xu;Shirong Yan;Liwu Fu
ATP结合盒（ABC）转运蛋白的过度表达是导致肿瘤多药耐药（MDR）的根本原因，MDR是许多肿瘤化疗成功的重要障碍。因此，抑制ABC转运蛋白的活性可能是规避MDR的合理方法。Olmutinib是一种表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），已在韩国获批用于治疗晚期EGFR T790 M阳性非小细胞肺癌（NSCLC）。在这里，我们发现奥木替尼显著增加了ABCG 2过表达细胞对化疗药物的敏感性。此外，奥莫替尼还可以增加多柔比星（DOX）和罗丹明123（Rho 123）在ABC转运蛋白亚家族G成员2（ABCG 2）过表达细胞中的滞留。此外，发现奥木替尼可刺激ATP酶活性，并抑制ABCG 2与[125 I]-碘芳基叠氮吡唑嗪（IAAP）的光标记。然而，奥莫替尼既不改变ABCG 2在蛋白和mRNA水平的表达，也不阻断EGFR、Her-2下游AKT和ERK信号传导。重要的是，奥莫替尼增强了拓扑替康抑制S1-MI-80细胞异种移植物生长的功效。以上结果表明，奥莫替尼通过与ABCG 2的ATP结合位点结合，增加细胞内化疗药物蓄积，逆转ABCG 2介导的MDR。我们的研究结果鼓励进一步临床研究奥莫替尼与常规化疗药物联合治疗ABCG 2过表达的癌症患者。
Overexpressing of ATP-binding cassette (ABC) transporters is the essential cause of multidrug resistance (MDR), which is a significant hurdle to the success of chemotherapy in many cancers. Therefore, inhibiting the activity of ABC transporters may be a logical approach to circumvent MDR. Olmutinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which has been approved in South Korea for advanced EGFR T790M-positive non-small cell lung cancer (NSCLC). Here, we found that olmutinib significantly increased the sensitivity of chemotherapy drug in ABCG2-overexpressing cells. Furthermore, olmutinib could also increase the retention of doxorubicin (DOX) and rhodamine 123 (Rho 123) in ABC transporter subfamily G member 2 (ABCG2)-overexpressing cells. In addition, olmutinib was found to stimulate ATPase activity and inhibit photolabeling of ABCG2 with [125I]-iodoarylazidoprazosin (IAAP). However, olmutinib neither altered ABCG2 expression at protein and mRNA levels nor blocked EGFR, Her-2 downstream signaling of AKT and ERK. Importantly, olmutinib enhanced the efficacy of topotecan on the inhibition of S1-MI-80 cell xenograft growth. All the results suggest that olmutinib reverses ABCG2-mediated MDR by binding to ATP bind site of ABCG2 and increasing intracellular chemotherapeutic drug accumulation. Our findings encouraged to further clinical investigation on combination therapy of olmutinib with conventional chemotherapeutic drugs in ABCG2-overexpressing cancer patients.