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.
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Abstract9-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.
CitationCancer Lett. 2006, 244 (1):101-108
DescriptionDietary modulation of carcinogenesis-related pathwaysDietary item or component studied: 9cRA (9-cis-retinoic acid)Pathways studied: upregulation of RAR-β and suppression of COX-2 at the transcriptional levelStudy type (in vitro, animals, humans): male A/J miceTissue/biological material/sample size: 20mg lung tissueMode of exposure (if in vivo) (acute, chronic, root of exposure): i.p. injectionsImpact on pathway (including dose-response): the group receiving NNK alone had significantly higher tumour incidence and tumor multiplicity (P! 0.001 for bothTreatment with the COX-2 inhibitor drug significantly decreased incidence of tumors (75% decrease, P! 0.05), while treatment with 9cRA showed a trend toward decreased tumor incidence (40% decrease, PZ 0.078).Treatment with the COX-2 inhibitor drug resulted in an 88% lower tumor multiplicity (0.17G 0.39 tumors/slide, PZ0.001), while treatment with 9cRA resulted in a 48% decline in average number of tumors (0.73G1.03 tumors/slide, P! 0.05).No change in RAR-b expression with carcinogen treatment, 9cRA supplementation increased mRNA of RAR-b in lung tissue by 38%, compared to the group receiving carcinogen injection alone (P!0.05). KEYWORDS CLASSIFICATION: antagonists & inhibitors;Aging;Agriculture;Animals;Antineoplastic Agents;Biology;Boston;chemically induced;Carcinogens;Cell Transformation,Neoplastic;Cyclooxygenase 2;Cyclooxygenase 2 Inhibitors;drug effects;dietary modulation of cancer & cancer biomarkers;dietary modulation of carcinogenesis-related pathways;Dietary Supplements;Disease Models,Animal;Lung;Lung Neoplasms;metabolism;mortality;Male;Membrane Proteins;Mice;Mice,Inbred A;Nitrosamines;pharmacology;prevention & control;Proteins;Pyrazoles;Receptors,Retinoic Acid;Research;Sulfonamides;therapeutic use;toxicity;Tretinoin;United States;Washington.