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Celecoxib prevents colitis associated colon carcinogenesis: An upregulation of apoptosis

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Abstract

Background

Uncontrolled cell proliferation and suppressed apoptosis are the critical events transforming a normal cell to a cancerous one wherein the inflammatory microenvironment supports this oncogenic transformation. The process of colon carcinogenesis may be aggravated in chronic inflammatory conditions such as ulcerative colitis where non-steroidal anti-inflammatory drugs (NSAIDs) may effectively prevent the cellular and molecular events.

Methods

Western blots and immunofluorescent analysis of DNA mismatch repair enzymes, cell cycle regulators and pro- and anti-apoptotic proteins were performed in dextran sulfate sodium (DSS)-induced ulcerative colitis and 1,2-dimethyl benz(a)anthracene (DMH)-induced colon cancer. Also, apoptotic studies were done in isolated colonocytes using fluorescent staining and in paraffin sections using TUNEL assay.

Results

An upregulation of cell cycle regulators: cyclin D1/cdk4 and cyclin E/cdk2 and anti-apoptotic Bcl-2, along with the suppression of DNA repair enzymes: MLH1 and MSH2; tumour suppressors: p53, p21and Rb and pro-apoptotic proteins: Bax and Bad were observed in the DSS, DMH and DSS + DMH groups. Proliferating cell nuclear antigen (PCNA) was also overexpressed in these groups. The ultimate executioner of the apoptotic pathway; caspase-3, was suppressed in these groups. Apoptotic studies in colonocytes and paraffin sections revealed suppressed apoptosis in these groups. These effects were corrected with the administration of a second generation NSAID, celecoxib along with the treatment of DSS and DMH.

Conclusion

The chemopreventive action of celecoxib in colitis mediated colon carcinogenesis may include the regulation of DNA mismatch repair enzymes, cell cycle check points, cell proliferation and apoptosis.

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Authors and Affiliations

  1. Department of Biophysics, Panjab University, Chandigarh, India

    Shruti Setia, Bimla Nehru & Sankar N. Sanyal

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  1. Shruti Setia
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  2. Bimla Nehru
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  3. Sankar N. Sanyal
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Correspondence to Sankar N. Sanyal.

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Setia, S., Nehru, B. & Sanyal, S.N. Celecoxib prevents colitis associated colon carcinogenesis: An upregulation of apoptosis. Pharmacol. Rep 66, 1083–1091 (2014). https://doi.org/10.1016/j.pharep.2014.07.001

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  • DOI: https://doi.org/10.1016/j.pharep.2014.07.001

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