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

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 o...

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Published in:Cancers 2019-03, Vol.11 (3), p.427
Main Authors: Sankaranarayanan, Ranjini, Valiveti, Chaitanya K, Kumar, D Ramesh, Van Slambrouck, Severine, Kesharwani, Siddharth S, Seefeldt, Teresa, Scaria, Joy, Tummala, Hemachand, Bhat, G Jayarama
Format: Article
Language:English
Subjects:
Amino acids
Anti-inflammatory agents
Cancer
Cell cycle
Cell growth
Cell proliferation
Colon
Colorectal carcinoma
Cyclin-dependent kinase
Cyclin-dependent kinase inhibitor p21
Cyclin-dependent kinase inhibitor p27
Enzymes
Flavonoids
Inflammation
Investigations
Kinases
Metabolites
Microflora
Oxidants
Small intestine
Trihydroxybenzoic acid
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Summary: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 and p27 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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers11030427