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

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

  • Cancers (Basel). 2019 Mar 26;11(3):427. doi: 10.3390/cancers11030427.
Ranjini Sankaranarayanan 1,  Chaitanya K Valiveti 2,  D Ramesh Kumar 3,  Severine Van Slambrouck 4,  Siddharth S Kesharwani 5,  Teresa Seefeldt 6,  Joy Scaria 7,  Hemachand Tummala 8,  G Jayarama Bhat 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA. ranjini.sankaranarayanan@sdstate.edu.
  • 2 Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA. chaitanya.valiveti@sdstate.edu.
  • 3 Current Address: Department of Entomology, University of Kentucky, Lexington, KY 40546, USA. rameshinsilico@gmail.com.
  • 4 Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD 57007, USA. severinevs@gmail.com.
  • 5 Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA. siddharth.kesharwani@sdstate.edu.
  • 6 Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA. teresa.seefeldt@sdstate.edu.
  • 7 Department of Veterinary and Biomedical Sciences, South Dakota State University, Brookings, SD 57007, USA. joy.scaria@sdstate.edu.
  • 8 Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA. hemachand.tummala@sdstate.edu.
  • 9 Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA. jayarama.gunaje@sdstate.edu.
PMID: 30917530 DOI: 10.3390/cancers11030427
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.

Keywords

CDKs and CDK inhibitors; colorectal cancer; cyclins; flavonoids and polyphenols.

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