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

Ranjini Sankaranarayanan,Siddharth Kesharwani,Severine Van Slambrouck,D Kumar,Hemachand Tummala,Joy Scaria,G Bhat,Chaitanya Valiveti,Teresa Seefeldt

doi:10.3390/cancers11030427

Ranjini Sankaranarayanan, Siddharth Kesharwani + Show 7 more

Open Access

https://doi.org/10.3390/cancers11030427

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Journal: Cancers	Publication Date: Mar 26, 2019
Citations: 42	License type: CC BY 4.0

Affiliation: South Dakota State University, University of Kentucky

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 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.

Highlights

More than one million people are diagnosed with colorectal cancer (CRC) worldwide every year, and it is the third most common cause of cancer death in the United States [1,2]
Activity, potently inhibited cancer cell proliferation independent of a functional SLC5A8. These results suggest that the flavonoid metabolite 2,4,6-THBA may mediate its anti-cancer effects through a CDKand SLC5A8-dependent pathway, whereas, 3,4-DHBA and 3,4,5-THBA are likely to exert their effect through a Cyclin Dependent Kinase (CDK)- and SLC5A8-independent pathway
In this research paper, using a variety of biochemical, molecular biology and computational approaches, we report that the flavonoid metabolite 2,4,6-trihydroxybenzoic acid (2,4,6-THBA) inhibits

Summary

Introduction

More than one million people are diagnosed with colorectal cancer (CRC) worldwide every year, and it is the third most common cause of cancer death in the United States [1,2]. CRC [3,4,5,6,7] Though these studies mainly focused on the therapeutic potential and activity of the parent. The backbone parent compounds, reports on the therapeutic role metabolites for their metabolites [8,9]. C, which is in turn backbone of flavonoids comprises of an aromatic ring A bound to a heterocyclic ring C, which is in attached to a third ring B ring through a carbon-carbon bond (Figure 1) [6,9].

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