9-cis-Retinoic acid inhibition of lung carcinogenesis in the A/J mouse model is accompanied by increased expression of RAR-beta but no change in cyclooxygenase-2.

Abstract

9-cis-Retinoic acid (9cRA) binds both retinoic acid receptors (RARs) and retinoid X receptors (RXRs) and has been shown to be a potential chemopreventive agent both in lung cancer cell culture studies and in clinical trials studying former smokers. However, direct evidence of the efficacy of 9cRA against lung tumor development in vivo is lacking. In the present study, we determined whether treatment with 9cRA has the potential to inhibit lung carcinogenesis by upregulating RAR-beta and down-regulating COX-2 expression in the A/J mouse lung cancer model. A/J mice (n=14-15/group) were treated as follows: (1) Control (Sham treated); (2) NNK (100mg NNK/kg body weight); (3) NNK+9cRA (15mg/kg diet); and (4) NNK+celecoxib (a COX-2-specific inhibitor, 500mg/kg diet). Tumor incidence, tumor multiplicity, RAR-beta mRNA, COX-2 mRNA, and COX-2 protein levels in lung samples of mice were determined 4 months after carcinogen injection. The results showed that mice receiving 9cRA supplementation had significantly lower tumor multiplicity (48% reduction, P<0.05) and showed a trend toward lower tumor incidence (40% reduction, P=0.078), as compared with the mice given NNK alone. Although, celecoxib treatment resulted in greater declines in tumor incidence and tumor multiplicity (75 and 88%, respectively, P<0.05), the chemoprotective effects of celecoxib were accompanied by increased mortality while 9cRA treatment resulted in no weight-loss associated toxicity or mortality. Supplementation with 9cRA was effective in increasing RAR-beta mRNA, but this increase was not accompanied by decreased levels of COX-2 mRNA or protein. These results suggest that 9cRA supplementation may provide protection against lung carcinogenesis and this effect may be mediated in part by 9cRA induction of RAR-beta, but not inhibition of COX-2 transcription.

• Authors: Heather Mernitz, Donald E Smith, Andrew X Zhu, Xiang-Dong Wang
• Journal: Cancer letters (Cancer Lett) Vol. 244 Issue 1 Pg. 101-8 (Nov 28 2006) ISSN: 0304-3835 [Print] Ireland
• PMID: 16413115 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Carcinogens
• Cyclooxygenase 2 Inhibitors
• Membrane Proteins
• Nitrosamines
• Pyrazoles
• Receptors, Retinoic Acid
• Sulfonamides
• retinoic acid receptor beta
• Alitretinoin
• Tretinoin
• 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
• Cyclooxygenase 2
• PTGS2 protein, human
• Celecoxib

Topics

• Alitretinoin
• Animals
• Antineoplastic Agents (therapeutic use)
• Carcinogens (toxicity)
• Celecoxib
• Cell Transformation, Neoplastic (drug effects)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Dietary Supplements
• Disease Models, Animal
• Lung (drug effects)
• Lung Neoplasms (chemically induced, metabolism, prevention & control)
• Male
• Membrane Proteins (antagonists & inhibitors, metabolism)
• Mice
• Mice, Inbred A
• Nitrosamines (toxicity)
• Pyrazoles (pharmacology)
• Receptors, Retinoic Acid (metabolism)
• Sulfonamides (pharmacology)
• Tretinoin (therapeutic use)