Dasatinib reverses the multidrug resistance of breast cancer MCF-7 cells to doxorubicin by downregulating P-gp expression via inhibiting the activation of ERK signaling pathway
Dasatinib reverses the multidrug resistance of breast cancer MCF-7 cells to doxorubicin by downregulating P-gp expression via inhibiting the activation of ERK signaling pathway
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DOI：
10.4161/15384047.2014.987062
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发表时间：
2015-01-01
影响因子：
3.6
通讯作者：
Liu, Kexin
中科院分区：
文献类型：
--
作者：
Chen, Ting;Wang, Changyuan;Liu, Kexin
肿瘤多药耐药（Multidrug resistance，MDR）是影响肿瘤化疗疗效的主要因素之一，其主要原因是药物外排转运蛋白如P-糖蛋白（P-glycoprotein，P-gp）过度表达。在本研究中，我们确定了达沙替尼（已被批准用于伊马替尼耐药的慢性粒细胞白血病（CML）和（Ph+）急性淋巴细胞白血病（ALL）治疗）对P-gp介导的MDR的影响。我们的研究结果表明，达沙替尼显着增加P-gp过表达的MCF-7/Adr细胞对阿霉素的敏感性在MTT法，从而导致阿霉素在MCF-7/Adr细胞的细胞毒性增强。此外，达沙替尼增加了MCF-7/Adr细胞中阿霉素的细胞内蓄积，抑制阿霉素的外排，并显著增强阿霉素诱导的MCF-7/Adr细胞凋亡。进一步的研究表明，达沙替尼改变mRNA的表达水平，P-gp的蛋白水平，和信号调节激酶（ERK）的磷酸化，在时间依赖性（24小时前）和剂量依赖性的方式在浓度产生MDR逆转。总之，达沙替尼通过下调P-gp表达逆转P-gp介导的MDR，这可能部分归因于ERK通路的抑制。达沙替尼与其他常规化疗药物联合使用时，可能在规避MDR方面发挥重要作用。
Multidrug resistance (MDR) is one of the major obstacles to the efficiency of cancer chemotherapy, which often results from the overexpression of drug efflux transporters such as P-glycoprotein (P-gp). In the present study, we determined the effect of dasatinib which was approved for imatinib resistant chronic myelogenous leukemia (CML) and (Ph+) acute lymphoblastic leukemia (ALL) treatment on P-gp-mediated MDR. Our results showed that dasatinib significantly increased the sensitivity of P-gp-overexpressing MCF-7/Adr cells to doxorubicin in MTT assays; thus lead to an enhanced cytotoxicity of doxorubicin in MCF-7/Adr cells. Additionally, dasatinib increased the intracellular accumulation, inhibited the efflux of doxorubicin in MCF-7/Adr cells, and significantly enhanced doxorubicin-induced apoptosis in MCF-7/Adrcells. Further studies showed that dasatinib altered the expression levels of mRNA, protein levels of P-gp, and the phosphorylation of signal-regulated kinase (ERK) both in time-dependent (before 24h) and dose-dependent manners at concentrations that produced MDR reversals. In conclusion, dasatinib reverses P-gp-mediated MDR by downregulating P-gp expression, which may be partly attributed to the inhibition of ERK pathway. Dasatinib may play an important role in circumventing MDR when combined with other conventional antineoplastic drugs.