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 p21^Cip1 and p27^Kip1 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.

Inflammatory bowel disease (IBD) is a chronic gut disorder that also elevates the risk of colorectal cancer (CRC). The global incidence and severity of IBD are rising, yet existing therapies often lead to severe side effects. Curcumin offers potent anti-inflammatory and chemotherapeutic properties. However, its clinical translation is hindered by rapid metabolism, as well as poor water solubility and stability, which limits its bioavailability. To address these challenges, we developed OC-S, a water-soluble and colon-targeted curcumin formulation that protects against colitis in mice. The current study advances OC-S as a dietary supplement by establishing its stability and compatibility with various commercial dietary products. Further, OC-S exhibited specific binding to inflamed colon tissue, potentially aiding in targeted drug retention at the inflammation site in colitis with diarrhea symptoms. We further investigated its efficacy in vivo and in vitro using a murine model of colitis and tumoroids from APC^min mice. OC-S significantly reduced colitis severity and pro-inflammatory cytokine expression compared with curcumin, even at very low doses (5 mg/kg/day). It also demonstrated higher anti-proliferative activity in CRC cells and colon cancer tumoroids vs. curcumin. Overall, this study demonstrated that OC-S effectively targets and retains water-soluble curcumin at the inflamed colon sites, while showing promise in addressing both colitis and colorectal cancer, which potentially paves the way for OC-S to advance into clinical development as a dietary product for both IBD and CRC.