Ceritinib Enhances the Efficacy of Substrate Chemotherapeutic Agent in Human ABCB1-Overexpressing Leukemia Cells In Vitro, In Vivo and Ex-Vivo.
Ceritinib Enhances the Efficacy of Substrate Chemotherapeutic Agent in Human ABCB1-Overexpressing Leukemia Cells In Vitro, In Vivo and Ex-Vivo.
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色瑞替尼在体外、体内和离体增强人 ABCB1 过表达白血病细胞中底物化疗药物的疗效。
DOI：
10.1159/000489655
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Liwu Fu
中科院分区：
文献类型：
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作者：
Li Yang;Manjun Li;Fang Wang;Chen Zhen;Min Luo;Xiaona Fang;Hong Zhang;Jianye Zhang;Qingshan Li;Liwu Fu
背景/目标：由ATP结合盒（ABC）转运蛋白ABCB 1、ABCC 1和ABCG 2等引发的多药耐药（MDR）是肿瘤化疗成功的关键障碍。目前尚无FDA批准的MDR调节剂可用于临床。Ceritinib是一种选择性ALK抑制剂，已被批准作为ALK阳性非小细胞肺癌的二线治疗药物。在这里，我们研究了塞瑞替尼在白血病相关MDR治疗中的作用。方法：MTT法检测细胞增殖;流式细胞仪检测细胞表面蛋白的表达及罗丹明123（Rh 123）和阿霉素（Dox）在细胞内的蓄积和外排。RT-PCR和Western blot分别检测基因表达和蛋白表达水平。结果如下：我们发现ceritinib在体外和体内模型中增强了ABCB 1过表达K562/adr白血病细胞中底物化疗药物的疗效，但在敏感的亲本K562白血病细胞和ABCC 1过表达HL-60/adr白血病细胞中均未增强。从机制上讲，ceritinib显著增加了Rh 123或Dox的细胞内蓄积，但在MDR逆转浓度下既不改变ABCB 1在蛋白和mRNA水平的表达，也不阻断AKT和ERK 1/2的磷酸化。重要的是，ceritinib还增加了Dox的细胞内积累，并增强了Dox在体外原代白血病细胞中的疗效。结论：我们的研究结果表明，塞瑞替尼在体外、体内和离体实验中增强了底物化疗药物对白血病细胞生长的抑制作用，这与阻断ABCB 1功能有关，将其底物常规化疗药物泵出，从而增加细胞内蓄积。提示塞瑞替尼与底物化疗药物联合应用可能是治疗ABCB 1介导MDR的耐药白血病患者的有效方法。
Background/aims: Multidrug resistance (MDR) triggered by ATP binding cassette (ABC) transporters, such as ABCB1, ABCC1, and ABCG2, is a key obstacle for successful cancer chemotherapy. There is currently no FDA-approved MDR modulator that can be used in clinic. Ceritinib, a selective ALK inhibitor, has been approved as the second-line treatment for ALK-positive non-small cell lung cancer. Here, we examined the role of ceritinib in leukemia associated MDR in therapy...Methods: The cell proliferation was detected by MTT assay. The flow cytometry was used to detect the expression of cell surface protein and to detect the accumulation and efflux of rhodamine 123 (Rh123) or doxorubicin (Dox) in cells. The RT-PCR and Western blot were performed to detect the gene expression and protein expression levels, respectively...Results: We found that ceritinib enhanced the efficacy of substrate chemotherapeutic agent in ABCB1-overexpressing K562/adr leukemia cells both in vitro and in vivo models, but neither in sensitive parental K562 leukemia cells nor in ABCC1-overexpressing HL-60/adr leukemia cells. Mechanistically, ceritinib significantly increased the intracellular accumulation of Rh123 or Dox but did neither alter ABCB1 expressions at both protein and mRNA levels nor block the phosphorylations of AKT and ERK1/2 at the concentration of MDR reversal. Importantly, ceritinib also increased the intracellular accumulation of Dox and enhanced the efficacy of Dox in primary leukemia cells in ex-vivo...Conclusion: Our results suggested that ceritinib enhanced the efficacy of substrate chemotherapeutic agent on inhibition of leukemia cell growth in vitro, in vivo and ex-vivo, which linked to block ABCB1 function, pumping out its substrate conventional chemotherapeutic agent, thereby increasing the intracellular accumulation. These suggest the combination of ceritinib and substrate chemotherapeutic drugs maybe an effective treatment of resistant leukemia patients with ABCB1-mediated MDR..