Salicylic acid metabolites and derivatives inhibit CDK activity: Novel insights into aspirin's chemopreventive effects against colorectal cancer
| Autor: | Hemachand Tummala, Rakesh Dachineni, G. Jayarama Bhat, Teresa Seefeldt, D. Ramesh Kumar, Ranjini Sankaranarayanan, Eduardo Callegari, Siddharth S. Kesharwani |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Metabolite salicylic acid colorectal cancer Pharmacology Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine CDKs and CDK inhibitors gentisic acid Cyclin-dependent kinase CDC2 Protein Kinase medicine Hydroxybenzoates chemoprevention Anticarcinogenic Agents Humans Cyclin B1 Protein Kinase Inhibitors polyphenols chemistry.chemical_classification Aspirin Kinase Cytochrome P450 Acetylation Articles HCT116 Cells 3. Good health salicylic acid binding protein Molecular Docking Simulation 030104 developmental biology Enzyme Oncology chemistry Mechanism of action 030220 oncology & carcinogenesis biology.protein gallic acid medicine.symptom Colorectal Neoplasms cyclins Salicylic acid medicine.drug |
| Zdroj: | International Journal of Oncology |
| ISSN: | 1791-2423 1019-6439 |
| Popis: | Aspirin's potential as a drug continues to be evaluated for the prevention of colorectal cancer (CRC). Although multiple targets for aspirin and its metabolite, salicylic acid, have been identified, no unifying mechanism has been proposed to clearly explain its chemopreventive effects. Our goal here was to investigate the ability of salicylic acid metabolites, known to be generated through cytochrome P450 (CYP450) enzymes, and its derivatives as cyclin dependent kinase (CDK) inhibitors to gain new insights into aspirin's chemopreventive actions. Using in vitro kinase assays, for the first time, we demonstrate that salicylic acid metabolites, 2,3-dihydroxy-benzoic acid (2,3-DHBA) and 2,5-dihydroxybenzoic acid (2,5-DHBA), as well as derivatives 2,4-dihydroxybenzoic acid (2,4-DHBA), 2,6-dihydroxybenzoic acid (2,6-DHBA), inhibited CDK1 enzyme activity. 2,3-DHBA and 2,6-DHBA did not inhibit CDK2 and 4; however, both inhibited CDK-6 activity. Interestingly, another derivative, 2,4,6-trihydroxybenzoic acid (2,4,6-THBA) was highly effective in inhibiting CDK1, 2, 4 and 6 activity. Molecular docking studies showed that these compounds potentially interact with CDK1. Immunoblotting experiments showed that aspirin acetylated CDK1, and pre-incubation with salicylic acid and its derivatives prevented aspirin-mediated CDK1 acetylation, which supported the data obtained from molecular docking studies. We suggest that intracellularly generated salicylic acid metabolites through CYP450 enzymes within the colonic epithelial cells, or the salicylic acid metabolites generated by gut microflora may significantly contribute to the preferential chemopreventive effect of aspirin against CRC through inhibition of CDKs. This novel hypothesis and mechanism of action in aspirin's chemopreventive effects opens a new area for future research. In addition, structural modification to salicylic acid derivatives may prove useful in the development of novel CDK inhibitors in cancer prevention and treatment. |
| Databáze: | OpenAIRE |
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