Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas.
Drug Discovery Institute, University of Houston, Houston, Texas.
Med Res Rev. 2020 May;40(3):856-880. doi: 10.1002/med.21637. Epub 2019 Oct 6.
The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the best-documented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases, dementia and neurodegenerative diseases, heart failure and cardiovascular diseases, nephropathy, diabetes, obesity, and sterility. MDM2 inhibitors have been shown to have promising therapeutic efficacy for treating inflammation and other nonmalignant diseases in preclinical evaluations. Therefore, targeting MDM2 may represent a promising approach for treating and preventing these nonmalignant diseases. In addition, a better understanding of how MDM2 works in nonmalignant diseases may provide new biomarkers for their diagnosis, prognostic prediction, and monitoring of therapeutic outcome. In this review article, we pay special attention to the recent findings related to the roles of MDM2 in the pathogenesis of several nonmalignant diseases, the therapeutic potential of its downregulation or inhibition, and its use as a biomarker.
鼠双微体 2 (MDM2) 癌基因在人类癌症中发挥主要致癌作用；它不仅是 p53 肿瘤抑制因子的最佳有记录的负调节剂，而且还发挥 p53 非依赖性作用。人们越来越有兴趣开发基于 MDM2 的靶向治疗方法。已经在临床前模型中评估了几类 MDM2 抑制剂，其中一些已进入临床试验，主要用于癌症治疗。然而，也已经确定了 MDM2 的非致癌作用，表明 MDM2 参与许多慢性疾病和病症，如炎症和自身免疫性疾病、痴呆和神经退行性疾病、心力衰竭和心血管疾病、肾病、糖尿病、肥胖症和不育症。在临床前评估中，MDM2 抑制剂已显示出在治疗炎症和其他非恶性疾病方面具有有前景的治疗效果。因此，靶向 MDM2 可能代表治疗和预防这些非恶性疾病的一种有前途的方法。此外，更好地了解 MDM2 在非恶性疾病中的作用可能为这些疾病的诊断、预后预测和治疗效果监测提供新的生物标志物。在这篇综述文章中，我们特别关注与 MDM2 在几种非恶性疾病发病机制中的作用、其下调或抑制的治疗潜力以及作为生物标志物的用途相关的最新发现。
