Chemoprevention is the promising approach to reduce the occurrence of cancer. Chemopreventive agents slow, block, suppress, or reverse the effects of cancer causing factors. Chemopreventive agents may interfere with initiation, promotion, progression, or all stages of multistage carcinogenesis. A large number of compounds, both naturally occurring and synthetic, have been shown to prevent the occurrence of cancer in experimental animals. Recent studies in our laboratory have indicated that the topical application of sarcodiol, a semi-synthetic product produced by chemical modification of the marine natural product sarcophine, significantly decreased the incidence and multiplicity of skin papillomas in dimethylbenz(a)anthracene (DMBA)-initiated and 12-O- tetradecanoyl phorbol-13-acetate (TPA)-promoted carcinogenesis in female CD1 mice. The topical application of sarcodiol inhibited TPA-induced DNA synthesis. Sarcodiol pretreatment also induced apoptotic proteins, caspase 8 and 3, and decreased COX-2 levels in experimental mice. Based on these observations, we propose the hypothesis that sarcodiol prevents DMBA-initiated and TPA-promoted skin tumor development in CD-1 mice by decreasing cell proliferation and inducing apoptosis. These preliminary observations prompted the present investigation to study the chemopreventive effects of sarcodiol on UVB-induced skin cancer, more relevant to human skin cancer and to test the central hypothesis that antiproliferative and apoptotic effects of sarcodiol will lead to its chemopreventive effects against UVB- induced skin cancer.
The specific aims of the proposed investigation are to study the effects of sarcodiol on UVB-initiated, UVB- promoted and UVB-initiated and promoted skin cancer in female SKH1 hairless mice. We plan also to conduct a concentration-response and a time-response studies to determine the optimum concentration/time of application of sarcodiol, and to evaluate the effects of sarcodiol on COX-2 following UVB exposure, as a biomarker for inhibition of cell proliferations, and on caspases as biomarkers for induction of apoptosis.
The proposed project deals with skin cancer prevention, one of the most common cancers in the US. Sarcodiol has a very good potential to prevent UVB-induced skin cancer.
|Szymanski, Pawel T; Ahmed, Safwat A; Khalifa, Sherief et al. (2013) Chemopreventive effect of sarcophine-diol on NOR-1-induced TPA-promoted skin carcinogenesis in female HOS:HR-1 mice. Nat Prod Commun 8:153-4|
|Guillermo, Ruth F; Zhang, Xiaoying; Kaushik, Radhey S et al. (2012) Dose-response on the chemopreventive effects of sarcophine-diol on UVB-induced skin tumor development in SKH-1 hairless mice. Mar Drugs 10:2111-25|
|Szymanski, Pawel T; Muley, Pratik; Ahmed, Safwat A et al. (2012) Sarcophine-diol inhibits expression of COX-2, inhibits activity of cPLA2, enhances degradation of PLA2 and PLC(?)1 and inhibits cell membrane permeability in mouse melanoma B16F10 cells. Mar Drugs 10:2166-80|