Effect of ceritinib (LDK378) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo.
Effect of ceritinib (LDK378) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo.
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色瑞替尼（LDK378）对 ABCB1 和 ABCG2 过表达细胞体内外增强化疗药物的作用
DOI：
10.18632/oncotarget.5989
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发表时间：
2015-12-29
期刊：
影响因子：
--
通讯作者：
Fu L
中科院分区：
文献类型：
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作者：
Hu J;Zhang X;Wang F;Wang X;Yang K;Xu M;To KK;Li Q;Fu L
多药耐药（MDR）是肿瘤化疗失败的主要原因。ATP结合盒（ABC）转运蛋白，特别是ABCB 1，ABCC 1和ABCG 2的过表达，通过将抗癌药物从癌细胞中泵出而在介导MDR中起关键作用。Ceritinib（LDK 378）是间变性淋巴瘤激酶（ALK）的第二代酪氨酸激酶抑制剂，目前正在进行治疗非小细胞肺癌的III期临床试验。在这里，我们发现ceritinib在体外和体内显着增强化疗药物在ABCB 1或ABCG 2过表达癌细胞中的疗效。Ceritinib通过抑制转运蛋白过表达细胞中ABCB 1或ABCG 2介导的药物外排，显著增加化疗药物（如多柔比星（DOX））的细胞内蓄积。从机制上讲，色瑞替尼可能是ABCB 1和ABCG 2的竞争性抑制剂，因为它与[125 I]-碘芳基叠氮吡唑嗪竞争转运蛋白的光亲和标记。另一方面，在转运蛋白抑制浓度下，ceritinib未改变ABCB 1和ABCG 2的表达水平以及AKT和ERK 1/2的磷酸化状态。因此，研究结果提倡在化学难治性癌症患者中进一步临床研究ceritinib和其他常规化疗药物的联合化疗。
Multidrug resistance (MDR) is the leading cause of treatment failure in cancer chemotherapy. The overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2, play a key role in mediating MDR by pumping anticancer drugs out from cancer cells. Ceritinib (LDK378) is a second-generation tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) currently in phase III clinical trial for the treatment of non-small cell lung cancer. Here, we found that ceritinib remarkably enhanced the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 over-expressing cancer cells in vitro and in vivo. Ceritinib significantly increased the intracellular accumulation of chemotherapeutic agents such as doxorubicin (DOX) by inhibiting ABCB1 or ABCG2-mediated drug efflux in the transporters-overexpressing cells. Mechanistically, ceritinib is likely a competitive inhibitor of ABCB1 and ABCG2 because it competed with [125I]-iodoarylazidoprazosin for photo affinity labeling of the transporters. On the other hand, at the transporters-inhibiting concentrations, ceritinib did not alter the expression level of ABCB1 and ABCG2, and phosphorylation status of AKT and ERK1/2. Thus the findings advocate further clinical investigation of combination chemotherapy of ceritinib and other conventional chemotherapeutic drugs in chemo-refractory cancer patients.