细胞周期蛋白依赖激酶
细胞周期
癌症研究
生物
CDK抑制剂
激酶
细胞周期蛋白
克隆形成试验
细胞周期蛋白依赖激酶1
细胞凋亡
细胞生物学
生物化学
作者
Sonal M Manohar,Kalpana Joshi
出处
期刊:Current Molecular Pharmacology
[Bentham Science]
日期:2022-12-01
卷期号:15 (7): 1024-1033
被引量:3
标识
DOI:10.2174/1874467215666220124125809
摘要
Colorectal cancer (CRC) is the third leading cause of cancer death worldwide, and its incidence is steadily rising in developing nations. Cell cycle aberrations due to deregulation of cyclin dependent kinases (CDKs) and cyclins are common events during colorectal carcinogenesis. Yet, efficacy of multitarget CDK inhibitors as therapeutic agents has not been much explored against CRC.The anticancer potential of multitarget CDK inhibitor riviciclib (also known as P276-00), was investigated against CRC cell lines of varied genetic background.Cytotoxicity of riviciclib - potent CDK1, CDK4 and CDK9-specific inhibitor was evaluated in vitro. Further, its effect on clonogenic potential, cell cycle, apoptosis and transcription was tested using colony forming assay, flow cytometry and western blot analysis, respectively. Also, efficacy of riviciclib in combination with standard chemotherapeutic agents was assessed. Dependency of CRC cells on specific CDKs for their survival was confirmed using siRNA studies.Riviciclib exerted significant cytotoxicity against CRC cells and inhibited their colony forming potential. It induced apoptosis along with inhibition of cell cycle CDKs and cyclins as well as transcriptional CDKs and cyclins. Moreover, dual combination of riviciclib with standard chemotherapeutic drugs exhibited synergism in CRC cells. siRNA studies indicated that CRC cells are dependent on specific CDKs for their survival which are targets of riviciclib.This study provides evidence that multitarget CDK inhibitors can serve as promising therapeutic agents against CRC alone or in combination.
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