Carcinogenesis Advance Access published online on January 6, 2005
Carcinogenesis, doi:10.1093/carcin/bgi012
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1 Department of Pharmacology, Faculty of Medicine, Zhejiang University, Hangzhou, China; Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China
* To whom correspondence should be addressed. Previous studies indicate that the arachidonic acid-metabolizing enzymes COX-2 and 5-LOX are over-expressed during the process of colonic adenoma formation promoted by cigarette smoke. The aims of the present study were to investigate whether there exists a relationship between COX-2 and 5-LOX, and whether dual inhibition of COX-2 and 5-LOX has an anti-carcinogenic effect in the colonic tumorigenesis promoted by cigarette smoke. Results showed that pretreating colon cancer cells with cigarette smoke extract (CSE) promoted colon cancer growth in the nude mouse xenograft model. Inhibition of COX-2 or 5-LOX reduced the tumor size. In the group treated with COX-2-inhibitor, the PGE2 level decreased while the LTB4 level increased. In contrast, in the 5-LOX-inhibitor treated group, the LTB4 level was reduced and the PGE2 level was unchanged. However, combined treatment with both COX-2 and 5-LOX inhibitors further inhibited the tumor growth promoted by CSE over treatment with either COX-2-inhibitor or 5-LOX-inhibitor alone. This was accompanied by the down-regulation of PGE2 and LTB4. In an in vitro study, we found that the action of CSE on colon cancer cells was mediated by 5-LOX DNA de-methylation. In summary, these results indicate that inhibition of COX-2 may lead to a shunt of arachidonic acid metabolism towards the leukotriene pathway during colonic tumorigenesis promoted by CSE. Suppression of 5-LOX did not induce such a shunt and produced a better response. Therefore, 5-LOX inhibitor is more effective than COX-2 inhibitor, and blocker of both COX-2 and 5-LOX may present a superior anti-cancer profile in cigarette smokers.
Received October 19, 2004
Revised December 10, 2004
Accepted December 18, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Dual inhibition of 5-LOX and COX-2 suppresses colon cancer formation promoted by cigarette smoke
2 Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China
3 Department of Physiology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China
4 Department of Medicine, Faculty of Medicine, The University of Hong Kong, Hong Kong, China
5 Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Centre of Infection and Immunology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China
C. H. Cho, E-mail: chcho{at}hkusua.hku.hk
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