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Inhibition of 11beta-hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans.
- Source :
-
Journal of Clinical Investigation . Apr2009, Vol. 119 Issue 4, p876-885. 10p. 8 Color Photographs, 4 Black and White Photographs, 1 Diagram, 1 Chart, 8 Graphs. - Publication Year :
- 2009
-
Abstract
- Colorectal cancer (CRC) is a leading cause of cancer death, yet primary prevention remains the best approach to reducing overall morbidity and mortality. Studies have shown that COX-2-derived PGE2 promotes CRC progression, and both nonselective COX inhibitors (NSAIDs) and selective COX-2 inhibitors (such as glucocorticoids) reduce the number and size of colonic adenomas. However, increased gastrointestinal side effects of NSAIDs and increased cardiovascular risks of selective COX-2 inhibitors limit their use in chemoprevention of CRC. We found that expression of 11beta-hydroxysteroid dehydrogenase type II (11betaHSD2), which converts active glucocorticoids to inactive keto-forms, increased in human colonic and Apc+/min mouse intestinal adenomas and correlated with increased COX-2 expression and activity. Furthermore, pharmacologic inhibition or gene silencing of 11betaHSD2 inhibited COX-2-mediated PGE2 production in tumors and prevented adenoma formation, tumor growth, and metastasis in mice. Inhibition of 11betaHSD2 did not reduce systemic prostacyclin production or accelerate atherosclerosis in mice, thereby avoiding the major cardiovascular side effects seen with systemic COX-2 inhibitors. Therefore, 11betaHSD2 inhibition represents what we believe to be a novel approach for CRC chemoprevention and therapy by increasing tumor glucocorticoid activity, which in turn selectively blocks local COX-2 activity. [ABSTRACT FROM AUTHOR]
- Subjects :
- *COLON cancer
*GLUCOCORTICOIDS
*GENE expression
*GENE silencing
*LABORATORY mice
*METASTASIS
*ATHEROSCLEROSIS
*ADENOMA prevention
*COLON tumor prevention
*ADENOCARCINOMA
*ADENOMA
*ANIMAL experimentation
*BIOLOGICAL models
*CELL lines
*CELL receptors
*COLON tumors
*ENZYME inhibitors
*GENES
*HYDROCARBONS
*MICE
*NONSTEROIDAL anti-inflammatory agents
*NUCLEOTIDES
*ONCOGENES
*OXIDOREDUCTASES
*RESEARCH funding
*RNA
*CYCLOOXYGENASE 2
*PATHOLOGIC neovascularization
*CHEMICAL inhibitors
*PHARMACODYNAMICS
*PREVENTION
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 119
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- 37557316
- Full Text :
- https://doi.org/10.1172/JCI37398