Abstract 5262: The inhibitory effect of combinations of curcumin, ursolic acid, and metformin on skin tumor promotion by TPA
Authors: Tremmel Lisa , Rho Okkyung , DiGiovanni John 
Published: July 2017

Abstract
The purpose of this study was to examine the effects of combinations of ursolic acid (UA), curcumin (Curc), and metformin (Met) for potential synergistic chemopreventive activity to inhibit tumor promotion using the mouse two-stage skin carcinogenesis model. UA and Curc have been shown to inhibit tumorigenesis in several mouse models, and both have been shown to inhibit mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). The anti-cancer activity of these phytochemicals is due to their anti-inflammatory, anti-oxidant, and anti-proliferative effects. These effects are accomplished by acting on a broad spectrum of signaling pathways. Met has also been shown to have anti-cancer activity. In retrospective studies, type II diabetes patients taking Met have been shown to have a decreased cancer incidence. Met has also been shown to inhibit mouse skin tumor promotion by TPA. Met activates AMP-activated protein kinase (AMPK), which in turn inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling. mTORC1 is a key kinase involved in the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, one of the most commonly altered pathways in human tumors.
In initial short-term experiments (mice treated twice weekly for two weeks with TPA), combinations of UA and Curc pretreated topically inhibited TPA-induced activation of epidermal NF-κB, Cox-2, epidermal growth factor receptor (EGFR) and JNK to a greater extent than either compound alone. Additionally, these compounds increased levels of AMPK and programmed cell death protein 4 (Pdcd4). The alterations in these signaling pathways by the combination of UA and Curc were associated with decreased epidermal proliferation and skin inflammation as assessed by measuring BrdU incorporation and inflammatory gene expression, respectively. Further studies using dietary administration of a combination of UA and Curc, as well as combinations of UA or Curc (in diet) with Met administered in the drinking water were conducted. These combinations produced greater inhibition of TPA-induced activation of epidermal NFκB, Cox-2, and EGFR than the compounds given alone. These combinations also decreased epidermal proliferation, again shown by an inhibition of BrdU incorporation. In addition to these data, the results from ongoing skin tumor experiments (mice initiated with DMBA and promoted twice weekly with TPA) using both topical administration and dietary administration of the various combinations will be presented. The current results indicate that certain combinations of UA, Curc and Met may inhibit mouse skin tumor promotion by TPA to a greater extent than the compounds alone. The ability of the combinations to work when given both topically as well as in the diet suggests the potential for broad applications for chemopreventive strategies.
Citation Format: Lisa Tremmel, Okkyung Rho, John DiGiovanni. The inhibitory effect of combinations of curcumin, ursolic acid, and metformin on skin tumor promotion by TPA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5262. doi:10.1158/1538-7445.AM2017-5262