Journal Article

Chemopreventive agents induce oxidative stress in cancer cells leading to COX-2 overexpression and COX-2-independent cell death

Yu Sun, Jie Chen and Basil Rigas

in Carcinogenesis

Volume 30, issue 1, pages 93-100
Published in print January 2009 | ISSN: 0143-3334
Published online October 2008 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgn242
Chemopreventive agents induce oxidative stress in cancer cells leading to COX-2 overexpression and COX-2-independent cell death

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Chemopreventive agents generate oxidative stress, which culminates in cell death and may be part of a general mechanism of chemoprevention. The redox-responsive cyclooxygenase (COX)-2, overexpressed during carcinogenesis, has been a target for cancer prevention. To assess the potential link between chemopreventive agents, oxidative stress and COX-2, we studied the chemopreventive sulindac and nitric oxide-donating aspirin (NO-ASA). Both generated oxidative stress and induced COX-2 in various cell lines, more prominently in dying cells. Two antioxidants and an inhibitor of NADPH oxidase abrogated the induction of COX-2 and cell death. Exogenous xanthine/xanthine oxidase, which produce O2·, had the same effect. Inhibition of caspases and cox-2 knockdown showed that COX-2 did not participate in reactive oxygen species (ROS) generation or cell death induction in response to NO-ASA. Our results support three potentially useful ideas: (i) the concept that ROS are a critical component of the action of chemopreventive agents; (ii) the notion that COX-2 may not be an ideal target for chemoprevention and (iii) the possibility that COX-2 may be overexpressed in cancer cells due to their state of oxidative stress. It is conceivable that, if further substantiated, these findings may inform the rational design of chemotherapeutic strategies, in particular the choice of agents in combination approaches.

Journal Article.  5200 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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