Cyclin-dependent kinases (CDKs) are the key regulators of cell cycle progression. CDKs are strictly regulated by CDK inhibitor (CDKi) including p53, p21, and p27, however, cancer cells exploit this regulatory mechanism to their own advantage of uncontrolled cell growth. Because of this, CDKs are considered a potential target for anti-cancer therapeutics. Fisetin is a naturally occurring flavonoid and has shown anticancer effects in a range of different cancers. Despite its anticancer efficacy, its molecular target is still unknown. Our <i>in-silico</i> target prediction suggested that fisetin could target multiple kinases. Based on this, we have screened fisetin for different kinase inhibition activities and found that it inhibits several CDKs including CDK1, 2, 4, 5, and 6 at nanomolar concentration. To tested its cellular activity in the head and neck cancer (HNC) model and found that treatment with fisetin strongly inhibits cell proliferation and arrests the HNC cells in the G1 phase, followed by apoptotic cell death. In an <i>in-vivo</i> experiment, we found that oral fisetin treatment restrained the tumor progression of FaDu and SAS xenografts in the nude mouse models. These results suggest that fisetin has the potential to be developed as a multi-kinase inhibitor. Moreover, detailed data related to kinase activity and its regulation by fisetin will be presented.

Fisetin inhibits multi-cyclin-dependent kinases in head and neck cancer cells

ACS Spring 2022

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