Srikumar Thejal, Padmanabhan Jaya
Morsani College of Medicine, University of South Florida, Tampa, Florida, 33612, USA.
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, 33612, USA.
Adv Exp Med Biol. 2016;929:209-228. doi: 10.1007/978-3-319-41342-6_9.
This chapter describes the potential use of flavopiridol, a CDK inhibitor with anti-inflammatory and anti-proliferative activities, in the treatment of various chronic diseases. Flavopiridol arrests cell cycle progression in the G1 or G2 phase by inhibiting the kinase activities of CDK1, CDK2, CDK4/6, and CDK7. Additionally, it binds tightly to CDK9, a component of the P-TEFb complex (CDK9/cyclin T), and interferes with RNA polymerase II activation and associated transcription. This in turn inhibits expression of several pro-survival and anti-apoptotic genes, and enhances cytotoxicity in transformed cells or differentiation in growth-arrested cells. Recent studies indicate that flavopiridol elicits anti-inflammatory activity via CDK9 and NFκB-dependent signaling. Overall, these effects of flavopiridol potentiate its ability to overcome aberrant cell cycle activation and/or inflammatory stimuli, which are mediators of various chronic diseases.
本章描述了黄酮哌啶醇（一种具有抗炎和抗增殖活性的细胞周期蛋白依赖性激酶（CDK）抑制剂）在治疗各种慢性疾病中的潜在用途。黄酮哌啶醇通过抑制CDK1、CDK2、CDK4/6和CDK7的激酶活性，使细胞周期进程停滞在G1期或G2期。此外，它与P-TEFb复合物（CDK9/细胞周期蛋白T）的组成部分CDK9紧密结合，并干扰RNA聚合酶II的激活及相关转录。这进而抑制了几种促生存和抗凋亡基因的表达，并增强了转化细胞中的细胞毒性或生长停滞细胞的分化。最近的研究表明，黄酮哌啶醇通过CDK9和核因子κB（NFκB）依赖性信号传导发挥抗炎活性。总体而言，黄酮哌啶醇的这些作用增强了其克服异常细胞周期激活和/或炎症刺激的能力，而这些异常细胞周期激活和/或炎症刺激是各种慢性疾病的介质。
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