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

Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA

Current Address: Department of Entomology, University of Kentucky, Lexington, KY 40546, USA

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

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Abstract

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. View Full-Text

Keywords: colorectal cancer; cyclins; CDKs and CDK inhibitors; flavonoids and polyphenols

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MDPI and ACS Style

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. https://doi.org/10.3390/cancers11030427

AMA Style

Sankaranarayanan R, Valiveti CK, Kumar DR, Van slambrouck S, Kesharwani SS, Seefeldt T, Scaria J, Tummala H, Bhat GJ. 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(3):427. https://doi.org/10.3390/cancers11030427

Chicago/Turabian Style

Sankaranarayanan, Ranjini, Chaitanya K. Valiveti, D. R. Kumar, Severine Van slambrouck, Siddharth S. Kesharwani, Teresa Seefeldt, Joy Scaria, Hemachand Tummala, and G. J. Bhat. 2019. "The Flavonoid Metabolite 2,4,6-Trihydroxybenzoic Acid Is a CDK Inhibitor and an Anti-Proliferative Agent: A Potential Role in Cancer Prevention" Cancers 11, no. 3: 427. https://doi.org/10.3390/cancers11030427

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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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