In recent years, emerging evidence suggests that cancer chemopreventive agents when combined might be more effective than when given alone. Both UA and Res have been shown to reduce inflammation and tumor development in various tissues. In mouse skin, both compounds have been shown to block skin tumor promotion by TPA and reduce TPA-induced inflammation. In this study, we have further evaluated the effect of UA and Res on skin tumor promotion with emphasis on examining combinations of these agents. For these experiments, UA, Res and combinations of UA + Res were applied topically (various doses) prior to TPA treatment on mouse skin. The combination of UA + Res showed additive and possibly synergistic inhibition of TPA-induced epidermal hyperproliferation as assessed by both epidermal hyperplasia and BrdU labeling index. The effect of UA, Res and the combination of UA + Res on epidermal signaling pathways was also evaluated. The combination of UA + Res significantly inhibited activation of epidermal Akt, NF-κB, p38 MAPK, and JNK in response to TPA treatment compared to the treatment with the individual compounds. The combination of UA + Res also dramatically reduced the induction of epidermal Cox-2 by TPA. Notably, combined treatment with UA and Res induced a dramatic increased phosphorylation of AMPK-α suggesting that AMPK activation may also play a critical role in the ability of the combination to alter skin tumor promotion. Combination treatment during skin tumor promotion showed greater inhibition of tumor multiplicity than with either agent alone. In further experiments, the effect of UA, Res and UA + Res on proliferation of bulge-region keratinocyte stem cells (KSCs) was evaluated. Both UA and Res treatment inhibited TPA-induced proliferation and migration of bulge-region KSCs. Furthermore, the combination of UA + Res appeared to be more effective at blocking proliferation of these cells from the hair follicle when compared with the single compound-treated groups. Taken together, these data suggest that the combination of UA + Res has either additive or synergistic inhibitory effects on keratinocyte proliferation (including KSCs) and various signaling pathways. These effects may explain the greater inhibition of skin tumor promotion by the combination of UA and Res.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1596. doi:1538-7445.AM2012-1596

©2012 American Association for Cancer Research
2012