Abstract
The aim of this study was to determine the effects of selected phytochemicals such as resveratrol (RES), calcium D-glucarate (CG), and ursolic acid (URA) on the initiation and promotion stages of skin carcinogenesis. Our hypothesis was that these phytochemicals hinder various trademarks of tumor promotion_proliferation, resistance to apoptosis, and inflammation_and in combination may have an additive or synergistic effect. SENCAR mice (7-8 weeks old) with shaved backs each received one topical 5.1 µg dose of 7,12-dimethylbenz[a]antracene (DMBA) in 200 µl of acetone to initiate tumorigenesis, then after one month, two weekly doses of 2 µg 12-O-tetradecanoylphorbol-13 acetate (TPA) in 200 µl of acetone (tumor promotion) until sacrifice following the 14th week of TPA. The compounds were applied during either tumor initiation or promotion with animals receiving combinations of 2% dietary CG (w/w in AIN-93G diet) with either 2.5 \#956;mol RES in 200 \#956;l acetone or 1 \#956;mol URA in 200 \#956;l DMSO, which were applied topically 15 minutes prior to DMBA or each TPA treatment. Doses of these phytochemicals were chosen based on our results from a previous short-term study with the DMBA-induced complete carcinogenesis model. Although combinations of phytochemicals showed no additive or synergistic effect based on the parameters measured, we observed that URA applied during promotion was a strong inhibitor of carcinogenesis, with a 90% inhibition of tumor multiplicity through the 14th week of TPA. This treatment also reduced epidermal proliferation and hyperplasia by 47.8% and 40.6% respectively, as determined by BrdU and epidermal thickness measurements taken after the 8th week of TPA application. In addition, RT-PCR and western blot analyses were performed to quantify a number of biomarkers of tumor promotion including c-fos, COX-2, and TNF\#945;, among others. These results indicate that a number of phytochemicals had inhibitory effects on tumorigenesis, especially URA when applied during promotion and to a lesser extent RES when applied during initiation. URA applied during promotion inhibited transcription of a number of genes important for cell proliferation and inflammation, including c-fos (72.8% reduction) and COX-2 (65.1% reduction). Overall, these results show that URA is a potent inhibitor of skin tumor promotion and potential drug targets for skin cancer inhibition or therapy may be revealed by examining the association between URA and the molecular pathways involved in tumor promotion. Supported by NIH grants CA 102747 and P30 CA 54174-16S1
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3898.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO
RSS Feeds