Inhibition of skin tumor promotion by TPA using a combination of topically applied ursolic acid and curcumin

Mol Carcinog. 2019 Feb;58(2):185-195. doi: 10.1002/mc.22918. Epub 2018 Oct 28.


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 combination of ursolic acid (UA) and curcumin (Curc) for potential combinatorial inhibition of skin tumor promotion using the mouse two-stage skin carcinogenesis model. In short-term experiments, the combination of UA + Curc given topically prior to 12-O-tetradecanoylphorbol-13-acetate (TPA) significantly inhibited activation of epidermal EGFR, p70S6K, NF-κB p50, Src, c-Jun, Rb, and IκBα. Levels of c-Fos, c-Jun, and Cox-2 were also significantly reduced by the combination compared to the TPA treated group. The alterations in these signaling pathways by the combination of UA + Curc were associated with decreased epidermal proliferation as assessed by measuring BrdU incorporation. Significant effects were also seen with the combination on epidermal inflammatory gene expression and dermal inflammation, with the greatest effects on expression of IL-1β, IL-6, IL-22, and CXCL2. Furthermore, results from skin tumor experiments demonstrated that the combination of UA + Curc given topically significantly inhibited mouse skin tumor promotion by TPA to a greater extent than the individual compounds given alone. The greatest effects were seen on tumor free survival, tumor size, and tumor weight, although tumor incidence and multiplicity were also further reduced by the combination. These results demonstrate the potential cancer chemopreventive activity and mechanism(s) for the combination of UA + Curc.

Keywords: chemoprevention; combination; tumor promotion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Topical
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Chemokine CXCL2 / genetics
  • Chemokine CXCL2 / metabolism
  • Curcumin / administration & dosage*
  • Curcumin / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Interleukin-22
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Interleukins / genetics
  • Interleukins / metabolism
  • Mice
  • Signal Transduction / drug effects
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Tetradecanoylphorbol Acetate / adverse effects*
  • Treatment Outcome
  • Triterpenes / administration & dosage*
  • Triterpenes / pharmacology
  • Ursolic Acid
  • Xenograft Model Antitumor Assays


  • CXCL2 protein, human
  • Chemokine CXCL2
  • IL1B protein, human
  • IL6 protein, human
  • Interleukin-1beta
  • Interleukin-6
  • Interleukins
  • Triterpenes
  • Curcumin
  • Tetradecanoylphorbol Acetate