Natural products targeting the p53-MDM2 pathway and mutant p53: Recent advances and implications in cancer medicine.
Natural products targeting the p53-MDM2 pathway and mutant p53: Recent advances and implications in cancer medicine.
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DOI：
10.1016/j.gendis.2018.07.002
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发表时间：
2018-09
期刊：
影响因子：
6.8
通讯作者：
Zhang R
中科院分区：
文献类型：
--
作者：
Qin JJ;Li X;Hunt C;Wang W;Wang H;Zhang R
p53肿瘤抑制因子通过调控细胞周期阻滞、细胞凋亡、衰老和DNA修复，在控制癌症的发生和发展中发挥重要作用。MDM2致癌基因是p53的主要负调控因子，可抑制p53的活性并降低其蛋白稳定性。MDM2、p53和p53-MDM2通路是预防和/或治疗癌症的靶点。天然产物，特别是来自药用和食用植物的天然产物，是发现和开发新的治疗和预防人类癌症药物的丰富来源。许多天然产物衍生的MDM2抑制剂已经显示出对各种人类癌症的有效疗效。合成的小分子MDM2抑制剂大多数被设计为抑制MDM2-p53结合并激活p53，与之相反，许多天然产物抑制剂直接降低MDM2的表达和/或MDM2的稳定性，以p53依赖和p53独立的方式发挥其抗癌活性。最近，一些天然产物被报道针对癌症中的p53突变体。因此，鉴定靶向MDM2、p53突变体和p53-MDM2通路的天然产物可以为开发新的癌症化学预防和化疗药物提供有希望的策略。在这篇综述中，我们重点讨论了靶向p53-MDM2通路的抗癌天然产物的发现和开发的最新进展，强调了这些天然产物的功效、作用机制和特异性等几个新出现的问题。
The p53 tumor suppressor plays a major role in controlling the initiation and development of cancer by regulating cell cycle arrest, apoptosis, senescence, and DNA repair. The MDM2 oncogene is a major negative regulator of p53 that inhibits the activity of p53 and reduces its protein stability. MDM2, p53, and the p53-MDM2 pathway represent well-documented targets for preventing and/or treating cancer. Natural products, especially those from medicinal and food plants, are a rich source for the discovery and development of novel therapeutic and preventive agents against human cancers. Many natural product-derived MDM2 inhibitors have shown potent efficacy against various human cancers. In contrast to synthetic small-molecule MDM2 inhibitors, the majority of which have been designed to inhibit MDM2-p53 binding and activate p53, many natural product inhibitors directly decrease MDM2 expression and/or MDM2 stability, exerting their anticancer activity in both p53-dependent and p53-independent manners. More recently, several natural products have been reported to target mutant p53 in cancer. Therefore, identification of natural products targeting MDM2, mutant p53, and the p53-MDM2 pathway can provide a promising strategy for the development of novel cancer chemopreventive and chemotherapeutic agents. In this review, we focus our discussion on the recent advances in the discovery and development of anticancer natural products that target the p53-MDM2 pathway, emphasizing several emerging issues, such as the efficacy, mechanism of action, and specificity of these natural products.
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