Molecular pharmacology of multitarget cyclin-dependent kinase inhibitors in human colorectal carcinoma cells

被引：2

作者：

Manohar, Sonal M. ^{[1
]}

Joshi, Kalpana S. ^{[2
]}

机构：

[1] NMIMS Deemed Univ, Sunandan Divatia Sch Sci, Dept Biol Sci, Mumbai, India

[2] Cipla Ltd, Discovery Engine, Cipla R&D, Mumbai, India

来源：

EXPERT OPINION ON THERAPEUTIC TARGETS | 2023年 / 27卷 / 03期

关键词：

CDK inhibitors; colorectal cancer; Akt; Erk; HIF-1; NF-kappa B; STAT3; COLON-CANCER; GROWTH-FACTOR; IN-VITRO; ANTITUMOR PROPERTIES; APOPTOSIS; PROLIFERATION; CYTOTOXICITY; ACTIVATION; RECEPTOR; SURVIVAL;

D O I：

10.1080/14728222.2023.2199924

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Background: Colorectal cancer (CRC) is a leading cause of cancer death. Certain signaling pathways are implicated in colorectal carcinogenesis. Cyclin-dependent kinases (CDKs) are commonly hyperactivated in CRC and hence multitarget CDK inhibitors serve as promising therapeutic drugs against CRC. Objective: Off-target effects of multitarget CDK inhibitors with differential CDK inhibitory spectrum viz. P276-00 (also known as riviciclib), roscovitine and UCN-01 on CRC cell lines of varied genetic background were delineated. Method: Protein expression was analyzed for key signaling proteins by western blotting. beta-catenin localization was assessed using immunofluorescence. HIF-1 transcriptional activity and target gene expression were studied by reporter gene assay and RT-PCR respectively. Anti-migratory and anti-angiogenic potential was evaluated by wound healing assay and endothelial tube formation assay. Results: CDK inhibitors modulated various signaling pathways in CRC and for certain proteins showed a highly cell line-dependent response. Riviciclib and roscovitine inhibited HIF-1 transcriptional activity and HIF-1 alpha accumulation in hypoxic HCT116 cells. Both of these drugs also abrogated migration of HCT116 and in vitro angiogenesis in HUVECs. Conclusion: Anticancer activity of multitarget CDK inhibitors can be certainly attributed to their off-target effects and should be analyzed while assessing their therapeutic utility against CRC.

引用

页码：251 / 261

页数：11

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