Flavonoids have emerged as promising compounds capable of preventing
colorectal cancer (CRC) due to their
anti-oxidant and anti-inflammatory properties. It is hypothesized that the metabolites of
flavonoids are primarily responsible for the observed anti-
cancer effects owing to the unstable nature of the parent compounds and their degradation by colonic microflora. In this study, we investigated the ability of one metabolite,
2,4,6-trihydroxybenzoic acid (2,4,6-THBA) to inhibit
Cyclin Dependent Kinase (CDK) activity and
cancer cell proliferation. Using in vitro
kinase assays, we demonstrated that
2,4,6-THBA dose-dependently inhibited CDKs 1, 2 and 4 and in silico studies identified key
amino acids involved in these interactions. Interestingly, no significant CDK inhibition was observed with the structurally related compounds
3,4,5-trihydroxybenzoic acid (3,4,5-THBA) and
phloroglucinol, suggesting that orientation of the functional groups and specific
amino acid interactions may play a role in inhibition. We showed that cellular uptake of
2,4,6-THBA required the expression of functional SLC5A8, a monocarboxylic
acid transporter. Consistent with this, in cells expressing functional SLC5A8,
2,4,6-THBA induced CDK inhibitory
proteins p21Cip1 and p27Kip1 and inhibited cell proliferation. These findings, for the first time, suggest that the
flavonoid metabolite
2,4,6-THBA may mediate its effects through a CDK- and SLC5A8-dependent pathway contributing to the prevention of CRC.