Carbonyl Reductase 1 as a Novel Target of (-)-Epigallocatechin Gallate Against Hepatocellular Carcinoma
Carbonyl Reductase 1 as a Novel Target of (-)-Epigallocatechin Gallate Against Hepatocellular Carcinoma
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DOI：
10.1002/hep.23723
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发表时间：
2010-08-01
期刊：
影响因子：
13.5
通讯作者：
Yu, Long
中科院分区：
文献类型：
--
作者：
Huang, Weixue;Ding, Liya;Yu, Long
人羰基还原酶1（CBR 1）将抗肿瘤药物和蒽环类柔红霉素（DNR）转化为醇代谢产物柔红霉素醇（DNROL），其抗肿瘤活性和心脏毒性显著降低，这限制了DNR的临床应用。因此，抑制CBR 1可以增加DNR的疗效并降低毒性。在这里，我们报告，（）表没食子儿茶素没食子酸酯（EGCG）从绿色茶是一个有前途的抑制剂CBR 1。表没食子儿茶素没食子酸酯直接与CBR 1相互作用，并作为一个非竞争性抑制剂，相对于辅因子还原的烟酰胺腺嘌呤二核苷酸磷酸和底物靛红。抑制作用取决于pH，并且活性需要EGCG的没食子酸酯部分。分子模拟显示，EGCG占据了CBR 1的活性位点。此外，表没食子儿茶素没食子酸酯能特异性增强柔红霉素对高表达CBR 1的肝癌SMMC 7721细胞和相应异种移植物的抗肿瘤活性。我们还证明了EGCG可以克服稳定表达CBR 1的Hep 3B细胞对柔红霉素的耐药性，但不能通过RNA干扰CBR 1-HepG 2细胞。细胞提取物中代谢产物DNROL的水平与EGCG的水平呈负相关。最后，在小鼠SMMC 7721和Hep 3B细胞的人癌异种移植模型中，EGCG降低了DNR的心脏毒性。结论：这些结果有力地表明，EGCG可以抑制CBR 1活性，并增强抗癌药物DNR的有效性和降低心脏毒性。这些发现也表明，EGCG和DNR的组合可能代表一种新的方法，用于肝细胞癌的治疗或化学预防。（肝脏学2010;52：703-714）
Human carbonyl reductase 1 (CBR1) converts the antitumor drug and anthracycline daunorubicin (DNR) into the alcohol metabolite daunorubicinol (DNROL) with significantly reduced antitumor activity and cardiotoxicity, and this limits the clinical use of DNR. Inhibition of CBR1 can thus increase the efficacy and decrease the toxicity of DNR. Here we report that ()epigallocatechin gallate (EGCG) from green tea is a promising inhibitor of CBR1. EGCG directly interacts with CBR1 and acts as a noncompetitive inhibitor with respect to the cofactor reduced nicotinamide adenine dinucleotide phosphate and the substrate isatin. The inhibition is dependent on the pH, and the gallate moiety of EGCG is required for activity. Molecular modeling has revealed that EGCG occupies the active site of CBR1. Furthermore, EGCG specifically enhanced the antitumor activity of DNR against hepatocellular carcinoma SMMC7721 cells expressing high levels of CBR1 and corresponding xenografts. We also demonstrated that EGCG could overcome the resistance to DNR by Hep3B cells stably expressing CBR1 but not by RNA interference of CBR1-HepG2 cells. The level of the metabolite DNROL was negatively correlated with that of EGCG in the cell extracts. Finally, EGCG decreased the cardiotoxicity of DNR in a human carcinoma xenograft model with both SMMC7721 and Hep3B cells in mice. Conclusion: These results strongly suggest that EGCG can inhibit CBR1 activity and enhance the effectiveness and decrease the cardiotoxicity of the anticancer drug DNR. These findings also indicate that a combination of EGCG and DNR might represent a novel approach for hepatocellular carcinoma therapy or chemoprevention. (HEPATOLOGY 2010;52:703-714)