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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" (2019)

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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 University of Kentucky UKnowledge Entomology Faculty Publications Entomology 3-26-2019 The lF avonoid Metabolite 2,4,6-Trihydroxybenzoic Acid Is a CDK Inhibitor and an Anti-Proliferative Agent: A Potential Role in Cancer Prevention Ranjini Sankaranarayanan South Dakota State University Chaitanya K. Valiveti South Dakota State University Ramesh Kumar Dhandapani University of Kentucky, [email protected] Severine Van Slambrouck South Dakota State University Siddharth S. Kesharwani South Dakota State University See next page for additional authors Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/entomology_facpub Part of the Oncology Commons Repository Citation Sankaranarayanan, Ranjini; Valiveti, Chaitanya K.; Dhandapani, Ramesh Kumar; Van Slambrouck, Severine; Kesharwani, Siddharth S.; Seefeldt, Teresa; Scaria, Joy; Tummala, Hemachand; and Bhat, G. Jayarama, "The Flavonoid Metabolite 2,4,6-Trihydroxybenzoic Acid Is a CDK Inhibitor and an Anti-Proliferative Agent: A Potential Role in Cancer Prevention" (2019). Entomology Faculty Publications. 183. https://uknowledge.uky.edu/entomology_facpub/183 This Article is brought to you for free and open access by the Entomology at UKnowledge. It has been accepted for inclusion in Entomology Faculty Publications by an authorized administrator of UKnowledge. For more information, please contact [email protected]. Authors Ranjini Sankaranarayanan, Chaitanya K. Valiveti, Ramesh Kumar Dhandapani, Severine Van Slambrouck, Siddharth S. Kesharwani, Teresa Seefeldt, Joy Scaria, Hemachand Tummala, and G. Jayarama Bhat The Flavonoid Metabolite 2,4,6-Trihydroxybenzoic Acid Is a CDK Inhibitor and an Anti-Proliferative Agent: A Potential Role in Cancer Prevention Notes/Citation Information Published in Cancers, v. 11, issue 3, 427, p. 1-18. © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Digital Object Identifier (DOI) https://doi.org/10.3390/cancers11030427 This article is available at UKnowledge: https://uknowledge.uky.edu/entomology_facpub/183 cancers Article 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 1, Chaitanya K. Valiveti 1, D. Ramesh Kumar 2, Severine Van slambrouck 3, Siddharth S. Kesharwani 1, Teresa Seefeldt 1, Joy Scaria 4, Hemachand Tummala 1 and G. Jayarama Bhat 1,* 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; [email protected] (R.S.); [email protected] (C.K.V.); [email protected] (S.S.K.); [email protected] (T.S.); [email protected] (H.T.) 2 Current Address: Department of Entomology, University of Kentucky, Lexington, KY 40546, USA; [email protected] 3 Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD 57007, USA; [email protected] 4 Department of Veterinary and Biomedical Sciences, South Dakota State University, Brookings, SD 57007, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-605-688-6894 Received: 28 February 2019; Accepted: 22 March 2019; Published: 26 March 2019 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: colorectal cancer; cyclins; CDKs and CDK inhibitors; flavonoids and polyphenols 1. 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]. Studies conducted over the past two decades have clearly established chemo-preventive roles for flavonoids against CRC [3–7]. Though these studies mainly focused on the therapeutic potential and activity of the parent Cancers 2019, 11, 427; doi:10.3390/cancers11030427 www.mdpi.com/journal/cancers Cancers 2019, 11, 427 2 of 18 Cancers 2019, 11, x 2 of 18 compounds,parent compounds, limited limited reports existreports on exist the therapeutic on the therapeutic role for their role metabolitesfor their metabolites [8,9]. The backbone[8,9]. The ofbackbone flavonoids of flavonoids comprises comprises of an aromatic of an aromatic ring A boundring A tobound a heterocyclic to a hetero ringcyclic C, ring which C, which is in turnis in attachedturn attached to a third to a aromaticthird aromatic ring B ring through B through a carbon-carbon a carbon-carbon bond (Figure bond 1(Fig)[ 6ure,9]. 1) They [6,9] are. They further are classifiedfurther classified into anthocyanins, into anthocyanins, flavonols, flavonols, flavan-3-ols, flavan flavones,-3-ols, flavanones flavones, andflavanones isoflavones and based isoflavones on the individualbased on the functional individual groups function appendedal groups or attachedappended to or this attached backbone. to this The backbone. hydroxylation The hydroxylation pattern in the A-ringpattern is in mostly the A- conservedring is mostly whereas conserved the B-ring whereas can havethe B 1-ring to 3 hydroxylcan have groups1 to 3 hydroxyl [6]. Members groups of the[6]. flavonoidMembers familyof the flavonoid are highly family unstable are and highly are known unstable to undergoand are known light, temperature to undergo andlight, pH tempera dependentture degradationand pH dependent [10,11]; thedegradation number and [10,11] position; the of number –OH groups andare position inversely of correlated–OH groups with are stability inversely [12]. Flavonoidscorrelated with are reported stabilityto [12] be. moreFlavonoids stable are in acidic reported conditions to be more (pH stable < 4); however, in acidic at conditions neutral or (pH alkaline < 4); pHhowever, (pH > at 8, neutral as in the or intestine),alkaline pH they (pH undergo > 8, as in auto-degradation the intestine), they which undergo generates auto-degradation simpler phenolic which acidsgenerates [13]. simpler Additionally, phenolic owing acids [13] to their. Additionally, low absorption owing (1–15%)to their low in theabsorption small intestine, (1–15%) in flavonoids the small undergointestine, degradationflavonoids undergo in the colon degradation due to the inaction the colon of gut due microbiota to the action [9,14 of,15 gut]. Themicrobiota flavonoids [9,14,15] absorbed. The intoflavonoids the systemic absorbed circulation into the may systemic also revert circulation back tomay the also small revert intestine back as to conjugated the small metabolitesintestine as secretedconjugated in the metabolites bile fluid, secreted eventually in the reaching bile fluid, the colonic eventually microflora reaching [8]. the These colonic metabolites microflora may [8] undergo. These de-conjugationmetabolites may and undergo get re-exposed de-conjugation to the gastrointestinal and get re-expo (GI)sed epithelial to the gastrointestinal cells. Therefore, it(GI) is likelyepithelial that coloniccells. Therefore, stem/epithelial it is likely cells arethat exposed colonic to stem/epithelial these metabolites cells at relativelyare exposed high to concentrations. these metabolites In fact, at itrelatively is reported high that concentrations. phenolic acid In concentrations fact, it is reported obtained that from phenolic dietary acid sources concentrations in human obtained fecal matter from is relativelydietary sources high [ 16in ].human fecal matter is relatively high [16]. FigureFigure 1. Postulated degradation pathways of selected flavonoid flavonoid compounds to generate 2,4,6 2,4,6-THBA,-THBA, 4-HBA,4-HBA, 3,4-DHBA3,4-DHBA and 3,4,5-THBA.3,4,5-THBA. The parent flavonoidflavonoid compounds (labelled with roman numerals) undergoundergo autodegradationautodegradation or microbialmicrobial degradationdegradation to generategenerate unstableunstable intermediatesintermediates such as chalconeschalcones
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