缺氧通过抑制 MRP1 和 P-糖蛋白的表达，增强 MRP1 和 P-糖蛋白阻滞剂的化疗增敏作用，从而损害非小细胞肺癌细胞对阿霉素的耐药性。
Hypoxia can impair doxorubicin resistance of non-small cell lung cancer cells by inhibiting MRP1 and P-gp expression and boosting the chemosensitizing effects of MRP1 and P-gp blockers.
机构信息
Department of Life Sciences, National Chung Hsing University, 145, Hsing-Da Rd, Taichung, 40227, Taiwan.
Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
出版信息
Cell Oncol (Dordr). 2016 Oct;39(5):411-433. doi: 10.1007/s13402-016-0285-5. Epub 2016 Jun 15.
BACKGROUND
Non-small cell lung cancers (NSCLCs) frequently exhibit resistance to therapeutic drugs, which seriously hampers their treatment. Here, we set out to assess the roles of the multidrug resistance protein 1 (MRP1) and P-glycoprotein (P-gp) in the doxorubicin (DOX) resistance of NSCLC cells, as well as the putative therapeutic efficacy of MRP1 and P-gp blockers on DOX-treated NSCLC cells.
METHODS
The impact of DOX on cell survival, DOX efflux and MRP1 and P-gp expression was assessed in 5 different NSCLC-derived cell lines (parental CH27, A549, H1299, H460, and DOX resistant CH27) in the absence or presence of MK571 (MRP1 inhibitor) or Verapamil (P-gp inhibitor), under both normoxic and hypoxic conditions.
RESULTS
We found that in response to DOX treatment, NSCLC cells that express high levels of MRP1 and P-gp (such as CH27) showed a better DOX efflux and a higher DOX resistance. MK571 and Verapamil were found to abolish DOX resistance and to act as chemosensitizers for DOX therapy in all cell lines tested. We also found that hypoxia could inhibit MRP1 and P-gp expression in a HIF-1α-dependent manner, abolish DOX resistance and boost the chemosensitizer effect of MK571 and Verapamil on DOX treatment of all the NSCLC cells tested, except the DOX-resistant CH27 cells.
CONCLUSIONS
From our data we conclude that MRP1 and P-gp play critical roles in the DOX resistance of the NSCLC cells tested. MRP1 and P-gp targeted therapy using MK571, Verapamil, CoCl or ambient hypoxia appeared to be promising in abolishing the DOX efflux and DOX resistance of the NSCLC cells. The putative therapeutic efficacies of MRP1 and/or P-gp blockers on NSCLC cells are worthy of note.
背景
非小细胞肺癌（NSCLC）经常对治疗药物产生耐药性，严重阻碍了其治疗。在这里，我们评估了多药耐药蛋白 1（MRP1）和 P-糖蛋白（P-gp）在 NSCLC 细胞对多柔比星（DOX）耐药中的作用，以及 MRP1 和 P-gp 阻滞剂对 DOX 处理的 NSCLC 细胞的潜在治疗效果。
方法
在常氧和缺氧条件下，在 5 种不同的 NSCLC 衍生细胞系（亲本 CH27、A549、H1299、H460 和 DOX 耐药 CH27）中，评估 DOX 对细胞存活、DOX 外排以及 MRP1 和 P-gp 表达的影响，同时存在或不存在 MK571（MRP1 抑制剂）或维拉帕米（P-gp 抑制剂）。
结果
我们发现，在 DOX 处理下，表达高水平 MRP1 和 P-gp 的 NSCLC 细胞（如 CH27）表现出更好的 DOX 外排和更高的 DOX 耐药性。MK571 和维拉帕米被发现可以消除 DOX 耐药性，并在所有测试的细胞系中充当 DOX 治疗的化疗增敏剂。我们还发现，缺氧可以以 HIF-1α 依赖的方式抑制 MRP1 和 P-gp 的表达，消除 DOX 耐药性，并增强 MK571 和维拉帕米对所有测试的 NSCLC 细胞（除 DOX 耐药的 CH27 细胞外）对 DOX 治疗的化疗增敏作用。
结论
从我们的数据中，我们得出结论，MRP1 和 P-gp 在测试的 NSCLC 细胞对 DOX 的耐药性中起着关键作用。使用 MK571、维拉帕米、CoCl 或环境缺氧靶向治疗 MRP1 和 P-gp 似乎有望消除 NSCLC 细胞的 DOX 外排和 DOX 耐药性。MRP1 和/或 P-gp 阻滞剂对 NSCLC 细胞的潜在治疗效果值得注意。
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