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 (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-αThr172. 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.

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

“…A number of combinations of phytochemicals have now been tested and show increased anti‐tumor activity when combined compared to when given as individual compounds. For example, our laboratory has previously shown that the combination of UA + resveratrol (Res) inhibits skin tumor promotion to a greater extent than the compounds alone . Another study from our laboratory examined the combinations of UA + Curc, UA + Res, and Res + Curc given in the diet and demonstrated a synergistic inhibition of tumor growth in a prostate allograft tumor model .…”

In Vitro-In Vivo Dose Response of Ursolic Acid, Sulforaphane, PEITC, and Curcumin in Cancer Prevention

“…At 100 mg/kg bw UA significantly inhibited the growth of the cells noted in tumor weight. Further investigations, noted UA and OA increased expression of Bid and decreased the protein levels of MMP-2, Ki-67, and CD34 (12). Additionally, UA has been shown to inhibit proliferation and induce apoptosis in MTC-SK cells, a medullary thyroid carcinoma cell line) at 10 μM and 20 μM in vitro (13).…”

“…UA reduced TPA-induced inflammation and decreased the gene expression of IL-1, IL-22, and Cox-2 inflammatory genes. In addition, UA reduced binding of NF-Kβ, Egr-1, and AP-1 (12). Furthermore UA has recently been shown to inhibit cell growth and proliferation of pancreatic cell lines AsPC-1, MIA, PaCa-2, and Panc-28 cells at 5–20 μM in vitro (16).…”

Role of AMPK and PPARα in the anti‐skin cancer effects of ursolic acid

“…Recent studies from our laboratories using an in vivo model of skin tumor promotion have shown that UA and related triterpenes given topically can activate AMPK in the epidermis of mice treated with TPA . AMPK activation correlated with increased phosphorylation of ULK1 (Ser555) suggesting that AMPK activation by UA and related triterpenes may lead to induction of autophagic cell death.…”

“…The natural phytonutrient ursolic acid (UA) has been shown to have both anti‐cancer and anti‐diabetic effects in a variety of in vitro and in vivo systems. A number of studies indicated UA activates the energy sensor AMP‐activated protein kinase (AMPK), which has both anti‐cancer and anti‐diabetic properties.…”