Targeting tumor ubiquitin-proteasome pathway with polyphenols for chemosensitization.
Targeting tumor ubiquitin-proteasome pathway with polyphenols for chemosensitization.
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DOI：
10.2174/187152012802649978
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发表时间：
2012-10-01
影响因子：
2.8
通讯作者：
Dou QP
中科院分区：
文献类型：
--
作者：
Shen M;Chan TH;Dou QP
肿瘤耐药性的产生是实现化疗良好结果的最大障碍之一。在已探索的克服耐药性的各种策略中，当前化疗与植物多酚作为化学增敏剂的组合已成为一种有前途的策略。植物多酚是一组植物化学物质，其特征在于存在多个酚基团。机理研究表明多酚具有多个细胞内靶标，其中之一是蛋白酶体复合物。蛋白酶体是一种蛋白水解酶复合物，负责细胞内蛋白质降解，并已被证明在肿瘤生长和耐药性的发展中发挥重要作用。因此，植物多酚对蛋白酶体的抑制可能是其化学增敏作用的机制之一。已被鉴定具有蛋白酶体抑制活性的植物多酚包括(-)-表没食子儿茶素-3-没食子酸酯(EGCG)、金雀异黄素、木犀草素、芹菜素、白杨素、槲皮素、姜黄素和单宁酸。这些多酚在克服从癌、肉瘤到血液恶性肿瘤等多种肿瘤中对各种化疗药物的耐药性以及多药耐药性方面表现出显着的作用。对具有蛋白酶体抑制活性的多酚的体外和体内研究为支持它们可以作为癌症治疗的化学增敏剂的想法奠定了坚实的基础。需要进行深入的机制研究和确定最佳方案，以便最终将这一实验室概念转化为临床试验，从而真正有益于当前的化疗。
The development of tumor drug resistance is one of the biggest obstacles on the way to achieve a favorable outcome of chemotherapy. Among various strategies that have been explored to overcome drug resistance, the combination of current chemotherapy with plant polyphenols as a chemosensitizer has emerged as a promising one. Plant polyphenols are a group of phytochemicals characterized by the presence of more than one phenolic group. Mechanistic studies suggest that polyphenols have multiple intracellular targets, one of which is the proteasome complex. The proteasome is a proteolytic enzyme complex responsible for intracellular protein degradation and has been shown to play an important role in tumor growth and the development of drug resistance. Therefore, proteasome inhibition by plant polyphenols could be one of the mechanisms contributing to their chemosensitizing effect. Plant polyphenols that have been identified to possess proteasome-inhibitory activity include (−)-epigallocatechins-3-gallate (EGCG), genistein, luteolin, apigenin, chrysin, quercetin, curcumin and tannic acid. These polyphenols have exhibited an appreciable effect on overcoming resistance to various chemotherapeutic drugs as well as multidrug resistance in a broad spectrum of tumors ranging from carcinoma and sarcoma to hematological malignances. The in vitro and in vivo studies on polyphenols with proteasome-inhibitory activity have built a solid foundation to support the idea that they could serve as a chemosensitizer for the treatment of cancer. In-depth mechanistic studies and identification of optimal regimen are needed in order to eventually translate this laboratory concept into clinical trials to actually benefit current chemotherapy.
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