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Open AccessArticle

The Flavonoid Metabolite 2,4,6-Trihydroxybenzoic Acid Is a CDK Inhibitor and an Anti-Proliferative Agent: A Potential Role in Cancer Prevention

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Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA
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Current Address: Department of Entomology, University of Kentucky, Lexington, KY 40546, USA
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Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD 57007, USA
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Department of Veterinary and Biomedical Sciences, South Dakota State University, Brookings, SD 57007, USA
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(3), 427; https://doi.org/10.3390/cancers11030427
Received: 28 February 2019 / Revised: 16 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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. View Full-Text
Keywords: colorectal cancer; cyclins; CDKs and CDK inhibitors; flavonoids and polyphenols colorectal cancer; cyclins; CDKs and CDK inhibitors; flavonoids and polyphenols
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Sankaranarayanan, R.; Valiveti, C.K.; Kumar, D.R.; Van slambrouck, S.; Kesharwani, S.S.; Seefeldt, T.; Scaria, J.; Tummala, H.; Bhat, G.J. The Flavonoid Metabolite 2,4,6-Trihydroxybenzoic Acid Is a CDK Inhibitor and an Anti-Proliferative Agent: A Potential Role in Cancer Prevention. Cancers 2019, 11, 427.

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