title: Effect of Combined Treatment with Ursolic Acid and Resveratrol on Skin Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetate.
abstract: In this study, the effects of combining ursolic acid + resveratrol, for possible combined inhibitory effects on skin tumor promotion, were evaluated. Ursolic acid, resveratrol, and the combination of ursolic acid + resveratrol were applied topically prior to 12-O-tetracanoylphorbol-13-acetate (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 ursolic acid + resveratrol produced a greater inhibition of TPA-induced epidermal hyperproliferation. The combination of ursolic acid + resveratrol 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 with the groups treated with the individual compounds. Ursolic acid + resveratrol also induced a dramatic increase of p-AMPK-α(Thr172). Combined treatment with ursolic acid + resveratrol resulted in a greater inhibition of expression of proinflammatory cytokines, including Il1a, Il1b, and Il22. Furthermore, NF-κB, Egr-1, and AP-1 DNA binding activities after TPA treatment were dramatically decreased by the combination of ursolic acid + resveratrol. Treatment with ursolic acid + resveratrol 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 ursolic acid + resveratrol 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.
authors.affiliation: Division of Pharmacology and Toxicology in College of Pharmacy, The University of Texas at Austin, Austin, Texas.
authors.forename: Jiyoon
authors.initials: J
authors.lastname: Cho
authors.affiliation: Division of Pharmacology and Toxicology in College of Pharmacy, The University of Texas at Austin, Austin, Texas.
authors.forename: Okkyung
authors.initials: O
authors.lastname: Rho
authors.affiliation: Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Jacob
authors.initials: J
authors.lastname: Junco
authors.affiliation: Division of Pharmacology and Toxicology in College of Pharmacy, The University of Texas at Austin, Austin, Texas.
authors.forename: Steve
authors.initials: S
authors.lastname: Carbajal
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of California, San Diego, La Jolla, California.
authors.forename: Dionicio
authors.initials: D
authors.lastname: Siegel
authors.affiliation: Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Slaga
authors.affiliation: Division of Pharmacology and Toxicology in College of Pharmacy, The University of Texas at Austin, Austin, Texas. Department of Nutritional Sciences, The University of Texas at Austin, Austin, Texas. john.digiovanni@austin.utexas.edu.
authors.forename: John
authors.initials: J
authors.lastname: DiGiovanni
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D063646:Carcinogenesis; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003600:Cytosol / Q000378:metabolism; D005260:Female; D007249:Inflammation; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011485:Protein Binding; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D013267:Stilbenes / Q000008:administration & dosage*; D013755:Tetradecanoylphorbol Acetate / Q000737:chemistry*; D014315:Triterpenes / Q000008:administration & dosage*; D000097245:Ursolic Acid
chemical_list: D016588:Anticarcinogenic Agents; D000077185:Resveratrol; D013267:Stilbenes; D013755:Tetradecanoylphorbol Acetate; D014315:Triterpenes; D000097245:Ursolic Acid