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.