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Carcinogenesis
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The high affinity peroxisome proliferator-activated receptor-gamma agonist RS5444 inhibits both initiation and progression of colon tumors in azoxymethane-treated mice
Article first published online: 10 JUN 2008
DOI: 10.1002/ijc.23640
Copyright © 2008 Wiley-Liss, Inc.
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How to Cite
Su, W., Necela, B. M., Fujiwara, K., Kurakata, S., Murray, N. R., Fields, A. P. and Thompson, E. A. (2008), The high affinity peroxisome proliferator-activated receptor-gamma agonist RS5444 inhibits both initiation and progression of colon tumors in azoxymethane-treated mice. Int. J. Cancer, 123: 991–997. doi: 10.1002/ijc.23640
Publication History
- Issue published online: 17 JUN 2008
- Article first published online: 10 JUN 2008
- Manuscript Accepted: 17 MAR 2008
- Manuscript Received: 9 NOV 2007
Funded by
- Daiichi Sankyo, Inc.
- National Cancer Center, National Institutes of Health, United States Public Health Service. Grant Numbers: CA121349, CA94122, CA81436
- Abstract
- Article
- References
- Cited By
Keywords:
- PPARγ;
- colon carcinogenesis;
- colon cancer chemo-prevention;
- azoxymethane-induced colon tumors;
- nuclear receptors
Abstract
We evaluated RS5444, a thiazolidinedione high affinity PPARγ agonist, for the ability to inhibit colon carcinogenesis in azoxymethane (AOM)-treated mice. In our initial experiment, mice were treated with RS5444 during AOM treatment, and the drug was withdrawn 12 weeks after the last injection of AOM. RS5444 significantly inhibited aberrant crypt focus formation under these circumstances. Furthermore, exposure to RS5444 during the course of AOM treatment effectively blocked colon tumor formation after withdrawal of the agonist. PPARγ expression and nuclear localization were reduced in adenomas. RS5444 did not inhibit DNA synthesis in tumor cells, suggesting that PPARγ activity was impaired in adenomas. To test this hypothesis, pre-existing adenomas were treated with RS5444 for 16 weeks. We observed a slight, albeit not statistically significant, reduction in tumor incidence in RS5444-treated mice. However, histological examination revealed that tumors from RS5444-treated mice were of significantly lower grade, as evaluated by the extent of dysplasia. Furthermore, carcinoma in situ was observed in about one-third of control tumors, but was never observed in RS5444-treated tumors. We conclude that RS5444 inhibits both initiation and progression of colon tumors in the AOM model of sporadic colon carcinogenesis. © 2008 Wiley-Liss, Inc.