The effects of the combination of ursolic acid and curcumin administered topically and in the diet on skin tumor promotion by TPA

Prevention remains an important strategy to reduce the burden of cancer. One approach to prevent cancer is the use of phytochemicals in various combinations as safe and effective cancer preventative agents. The purpose of this study was to examine the effects of the topical combination of ursolic acid (UA) and curcumin (Curc) for potential combinatorial inhibition of skin tumor promotion using the mouse two-stage skin carcinogenesis model. Furthermore, UA, Curc and resveratrol (Res) were evaluated for their ability to inhibit skin tumor promotion when given in the diet alone and in combination. In short-term experiments, the combination of UA and Curc pretreated topically inhibited TPA-induced activation of epidermal EGFR, p70S6K, NF-κB p50, Src, c-Jun, Rb, c-Fos and IκBα. Levels of c-Fos, c-Jun and Cox-2 were also significantly reduced by the combination. The alterations in these signaling pathways by the combination of UA and Curc were associated with decreased epidermal proliferation as assessed by measuring BrdU incorporation. Significant effects were also seen with the combination on epidermal and inflammatory gene expression and dermal inflammation with the greatest effects on expression of IL-1β, IL-6, IL-22 and CXCL12. Furthermore, results from skin tumor experiments demonstrated that the combination of UA and Curc given topically significantly inhibited mouse skin tumor promotion by TPA to a greater extent than the individual compounds given alone. Initial short term experiments suggested UA, Curc and Res given in the diet alone or in combination inhibited TPA-induced EGFR, c-Jun, NF-κB p50, Cox-2 and Rb. Furthermore, Curc and Res, given alone and in combination with UA, inhibited TPA-induced hyperproliferation. However, in the two-stage skin carcinogenesis model none of the compounds given in the diet alone or in combination inhibited tumor multiplicity or tumor incidence at the dose give. Res alone did significantly inhibit tumor size and weight to levels comparable with Met, indicating it is inhibiting tumor growth, but not initial tumor development. These results demonstrate the potential cancer chemopreventive activity and mechanism(s) for the combination of topically applied UA and Curc