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

ABSTRACT

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. β-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-1α 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.

KEYWORDS:

• CDK inhibitors
• colorectal cancer
• Akt
• Erk
• HIF-1
• NF-kappa B
• STAT3

Acknowledgments

Authors would like to thank Piramal Life Sciences, Goregaon, Mumbai, India for supporting this research work and for providing necessary permissions to publish the same. We are grateful to the anonymous reviewers for improving quality of this article by providing their valuable inputs.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Author contributions

S. Manohar: study design, methodology, data analysis, writing – original draft, writing – review & editing. K. Joshi: conceptualization, design, formal analysis, writing – review & editing.

All authors have seen the final draft and approved its submission to Expert Opinion on Therapeutic Targets. All authors are willing to take responsibility for the data contained herein.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14728222.2023.2199924

Additional information

Funding

This manuscript was funded by Piramal Life Sciences Ltd., Mumbai, India