The incidence of skin cancer is equivalent to the incidence of malignancies in all other organs combined, and thus represents a major, and growing, public health problem. The constant increase in life expectancy, exposure to toxic environmental agents and changing dietary habits appear to be contributing factors for the increasing risk of skin cancer. Therefore, it is important to develop newer and more effective chemopreventive agents and strategies to address this public health issue. Grape seed proanthocyanidins (GSPs) have been shown to exert anticancer effects in various tumor models. Grape seeds are byproducts of grapes, and contain a larger fraction of proanthocyanidins which are primarily composed of dimers, trimers and oligomers of monomeric catechins. Here, we assessed the effect of dietary GSPs on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumor promotion in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated mouse skin. Administration of dietary GSPs (0.2 and 0.5%, w/w) supplemented with control AIN76A diet resulted in significant inhibition of TPA-induced skin tumor development in C3H/HeN mice in terms of reduction in percentage of mice with tumors (p<0.05), total number of tumors/group (p<0.01; n=20) and total tumor volume/tumor bearing mouse (p<0.01-0.001) compared to those mice which did not receive GSPs in the diet when analyzed at the termination of two-stage chemical carcinogenesis protocol. GSPs also inhibited malignant progression of papillomas into carcinomas. As, TPA-induced inflammatory responses, such as, edema, hyperplastic responses, inflammatory leukocyte infiltration, cyclooxygenase-2 (COX-2) expression and PGE2 production are conventionally used as markers of skin tumor promotion, we assessed the effect of GSPs on TPA-induced these biomarkers of inflammation. Immunohistochemical detection and western blot analysis revealed that GSPs significantly inhibit TPA-induced expression of COX-2, PGE2, PCNA and cyclin D1 in DMBA-initiated mouse skin and skin tumors. The results from short-term experiments revealed that dietary GSPs inhibited acute or multiple TPA treatment-induced edema, infiltration of inflammatory leukocytes, myeloperoxidase, COX-2 expression and PGE2 production in the mouse skin. Inhibitory effect of GSPs was also observed against other structurally different skin tumor promoters (anthralin, benzoylperoxide, mezerein)-induced inflammation in the mouse skin. Together, our results show for the first time that dietary GSPs inhibit chemical carcinogenesis in a two-stage mouse skin tumor model and that the inhibition of skin tumorigenesis by GSPs is associated with the inhibition of inflammatory responses caused by tumor promoters.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2976.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO