Open Access

Salicylic acid metabolites and derivatives inhibit CDK activity: Novel insights into aspirin's chemopreventive effects against colorectal cancer

  • Authors:
    • Rakesh Dachineni
    • D. Ramesh Kumar
    • Eduardo Callegari
    • Siddharth S. Kesharwani
    • Ranjini Sankaranarayanan
    • Teresa Seefeldt
    • Hemachand Tummala
    • G. Jayarama Bhat
  • View Affiliations

  • Published online on: October 19, 2017     https://doi.org/10.3892/ijo.2017.4167
  • Pages:1661-1673
  • Copyright: © Dachineni et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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-dihydroxybenzoic 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.

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December 2017
Volume 51 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

2016 Impact Factor: 3.079
Ranked #33/217 Oncology
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APA
Dachineni, R., Kumar, D.R., Callegari, E., Kesharwani, S.S., Sankaranarayanan, R., Seefeldt, T. ... Bhat, G.J. (2017). Salicylic acid metabolites and derivatives inhibit CDK activity: Novel insights into aspirin's chemopreventive effects against colorectal cancer. International Journal of Oncology, 51, 1661-1673. https://doi.org/10.3892/ijo.2017.4167
MLA
Dachineni, R., Kumar, D. R., Callegari, E., Kesharwani, S. S., Sankaranarayanan, R., Seefeldt, T., Tummala, H., Bhat, G. J."Salicylic acid metabolites and derivatives inhibit CDK activity: Novel insights into aspirin's chemopreventive effects against colorectal cancer". International Journal of Oncology 51.6 (2017): 1661-1673.
Chicago
Dachineni, R., Kumar, D. R., Callegari, E., Kesharwani, S. S., Sankaranarayanan, R., Seefeldt, T., Tummala, H., Bhat, G. J."Salicylic acid metabolites and derivatives inhibit CDK activity: Novel insights into aspirin's chemopreventive effects against colorectal cancer". International Journal of Oncology 51, no. 6 (2017): 1661-1673. https://doi.org/10.3892/ijo.2017.4167