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首页> 外文期刊>Journal of Nutritional Science and Vitaminology >Resveratrol reduces the hypoxia-induced resistance to doxorubicin in breast cancer cells
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Resveratrol reduces the hypoxia-induced resistance to doxorubicin in breast cancer cells

机译：白藜芦醇可降低缺氧诱导的乳腺癌细胞对阿霉素的耐药性

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Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is known to enhance the cyto-toxicity of the anticancer drug doxorubicin. On the other hand, breast cancer MCF-7 cells acquire resistance to doxorubicin under hypoxic conditions. In this study, we investigated the effect of resveratrol on hypoxia-induced resistance to doxorubicin in MCF-7 cells. Resver-atrol and its derivative 3,5-dihydroxy-4′-methoxy-trans-stilbene, but not 3,5-dimethoxy-4′-hydroxy-trans-stilbene, cancelled hypoxia-induced resistance to doxorubicin at a concentration of 10 mm. Carbonyl reductase 1 (CBR1) catalyzes the conversion of doxorubicin to its metabolite doxorubicinol, which is much less effective than doxorubicin. Hypoxia increased the expression of CBR1 at both mRNA and protein levels, and knockdown of CBR1 inhibited hypoxia-induced resistance to doxorubicin in MCF-7 cells. Knockdown of hypoxia-inducible factor (HIF)-1a repressed the hypoxia-induced expression of CBR1. Resveratrol repressed the expression of HIF-1a protein, but not HIF-1a mRNA, and decreased hypoxia-activated HIF-1 activity. Resveratrol repressed the hypoxia-induced expression of CBR1 at both mRNA and protein levels. Likewise, 3,5-dihydroxy-4′-methoxy-trans-stilbene decreased the hypoxia-induced expression of CBR1 protein, but not 3,5-dimethoxy-4′-hydroxy-trans-stilbene. Furthermore, resveratrol decreased the expression of HIF-1a protein even in the presence of the proteasome inhibitor MG132 in hypoxia. Theses results indicate that in MCF-7 cells, HIF-1a-increased CBR1 expression plays an important role in hypoxia-induced resistance to doxorubicin and that resveratrol and 3,5-dihydroxy-4′-methoxy-trans-stilbene decrease CBR1 expression by decreasing HIF-1a protein expression, perhaps through a proteasome-independent pathway, and consequently repress hypoxia-induced resistance to doxorubicin.
机译：已知白藜芦醇（3,4'，5-三羟基-反式-二苯乙烯）可增强抗癌药阿霉素的细胞毒性。另一方面，乳腺癌MCF-7细胞在低氧条件下获得对阿霉素的抗性。在这项研究中，我们研究了白藜芦醇对缺氧诱导的MCF-7细胞对阿霉素抗性的影响。白藜芦醇及其衍生物3,5-二羟基-4'-甲氧基-反式-二苯乙烯，但不是3,5-二甲氧基-4'-羟基-反式-二苯乙烯，在10的浓度下就消除了低氧诱导的对阿霉素的抗性毫米羰基还原酶1（CBR1）催化阿霉素向其代谢产物阿霉素的转化，阿霉素的功效远低于阿霉素。低氧增加了CBR1在mRNA和蛋白质水平上的表达，而敲低CBR1抑制了低氧诱导的MCF-7细胞对阿霉素的抗性。敲低缺氧诱导因子（HIF）-1a抑制了缺氧诱导的CBR1表达。白藜芦醇抑制HIF-1a蛋白的表达，但不抑制HIF-1a mRNA的表达，并降低缺氧激活的HIF-1活性。白藜芦醇在mRNA和蛋白水平上均抑制了低氧诱导的CBR1表达。同样，3,5-二羟基-4'-甲氧基-反式-二苯乙烯降低了缺氧诱导的CBR1蛋白的表达，但未降低3,5-二甲氧基-4'-羟基-反式-二苯乙烯的表达。此外，即使在低氧条件下存在蛋白酶体抑制剂MG132，白藜芦醇也会降低HIF-1a蛋白的表达。这些结果表明，在MCF-7细胞中，HIF-1a增加的CBR1表达在缺氧诱导的对阿霉素的抗性中起重要作用，而白藜芦醇和3,5-二羟基-4'-甲氧基-反式-二苯乙烯降低了CBR1的表达。降低HIF-1a蛋白的表达（可能通过不依赖蛋白酶体的途径），从而抑制低氧诱导的对阿霉素的抗性。

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