Jiyoon Cho, Okkyung Rho, Jacob Junco, Steve Carbajal, Dionicio Siegel, Thomas J Slaga, John DiGiovanni

In this study, the effects of combining ursolic acid (UA) + resveratrol (Res), for possible combined inhibitory effects on skin tumor promotion were evaluated. UA, Res and the combination of UA + Res were applied topically prior to TPA treatment on mouse skin to examine their effect on TPA-induced signaling pathways, epidermal hyperproliferation, skin inflammation, inflammatory gene expression and skin tumor promotion. The combination of UA + Res produced a greater inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced epidermal hyperproliferation. The combination of UA + Res inhibited TPA-induced signaling pathways, including EGFR, STAT3, Src, Akt, Cox-2, Fas, NF-κB, p38 MAPK, c-Jun, and JNK1/2 while increasing levels of tumor suppressors such as p21 and PDCD4 to a greater extent compared to the groups treated with the individual compounds. UA + Res also induced a dramatic increase of p-AMPK-α(T172). Combined treatment with UA + Res resulted in a greater inhibition of expression of proinflammatory cytokines including IL-1α, IL-1β, and IL-22. Furthermore, NF-κB, Egr-1, and AP-1 DNA binding activities after TPA treatment were dramatically decreased by the combination of UA + Res. Treatment with UA + Res during skin tumor promotion with TPA produced greater inhibition of tumor multiplicity and tumor size than with either agent alone. Collectively, the greater ability of the combination of UA + Res to inhibit skin tumor promotion was due to the greater inhibitory effects on growth factor and inflammatory signaling, skin inflammation and epidermal hyperproliferation induced by TPA treatment.