Qin Jiang-Jiang, Li Xin, Hunt Courtney, Wang Wei, Wang Hui, Zhang Ruiwen
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204, USA.
Center for Drug Discovery, University of Houston, Houston, TX, 77204, USA.
Genes Dis. 2018 Jul 20;5(3):204-219. doi: 10.1016/j.gendis.2018.07.002. eCollection 2018 Sep.
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.
p53肿瘤抑制因子通过调节细胞周期停滞、凋亡、衰老和DNA修复，在控制癌症的发生和发展中发挥着重要作用。MDM2癌基因是p53的主要负调控因子，它抑制p53的活性并降低其蛋白质稳定性。MDM2、p53以及p53-MDM2通路是预防和/或治疗癌症的充分记录的靶点。天然产物，尤其是来自药用和食用植物的天然产物，是发现和开发新型抗癌治疗和预防药物的丰富来源。许多天然产物衍生的MDM2抑制剂已显示出对各种人类癌症的强效疗效。与大多数旨在抑制MDM2-p53结合并激活p53的合成小分子MDM2抑制剂不同，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依赖性和p53非依赖性方式发挥其抗癌活性。最近，有报道称几种天然产物可靶向癌症中的突变p53。因此，鉴定靶向MDM2、突变p53和p53-MDM2通路的天然产物可为开发新型癌症化学预防和化疗药物提供一种有前景的策略。在本综述中，我们将讨论重点放在靶向p53-MDM2通路的抗癌天然产物的发现和开发的最新进展上，强调几个新出现的问题，如这些天然产物的疗效、作用机制和特异性。
