Meeran Syed M, Vaid Mudit, Punathil Thejass, Katiyar Santosh K
Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Carcinogenesis. 2009 Mar;30(3):520-8. doi: 10.1093/carcin/bgp019. Epub 2009 Jan 21.
Grape seed proanthocyanidins (GSPs) possess anticarcinogenic activities. Here, we assessed the effects 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%, wt/wt) supplemented with control AIN76A diet resulted in significant inhibition of TPA-induced skin tumor promotion in C3H/HeN mice. The mice treated with GSPs developed a significantly lower tumor burden in terms of the percentage of mice with tumors (P < 0.05), total number of tumors per group (P < 0.01, n = 20) and total tumor volume per tumor-bearing mouse (P < 0.01-0.001) as compared with the mice that received the control diet. GSPs also delayed the malignant progression of papillomas into carcinomas. As TPA-induced inflammatory responses are used routinely as markers of skin tumor promotion, we assessed the effect of GSPs on biomarkers of TPA-induced inflammation. Immunohistochemical analysis and western blotting revealed that GSPs significantly inhibited expression of cyclooxygenase-2 (COX-2), prostaglandin E(2) (PGE(2)) and markers of proliferation (proliferating cell nuclear antigen and cyclin D1) in both the DMBA-initiated/TPA-promoted mouse skin and skin tumors. In short-term experiments in which the mouse skin was treated with acute or multiple TPA applications, we found that dietary GSPs inhibited TPA-induced edema, hyperplasia, leukocytes infiltration, myeloperoxidase, COX-2 expression and PGE(2) production in the mouse skin. The inhibitory effect of GSPs was also observed against other structurally different skin tumor promoter-induced inflammation in the skin. Together, our results show that dietary GSPs inhibit chemical carcinogenesis in mouse skin and that the inhibition of skin tumorigenesis by GSPs is associated with the inhibition of inflammatory responses caused by tumor promoters.
葡萄籽原花青素（GSPs）具有抗癌活性。在此，我们评估了膳食GSPs对12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）诱导的、由7,12 - 二甲基苯并[a]蒽（DMBA）引发的小鼠皮肤肿瘤促进作用。在对照AIN76A饮食中补充膳食GSPs（0.2%和0.5%，重量/重量）可显著抑制C3H/HeN小鼠中TPA诱导的皮肤肿瘤促进作用。与接受对照饮食的小鼠相比，用GSPs处理的小鼠在有肿瘤的小鼠百分比（P < 0.05）、每组肿瘤总数（P < 0.01，n = 20）和每只荷瘤小鼠的肿瘤总体积（P < 0.01 - 0.001）方面肿瘤负担显著降低。GSPs还延缓了乳头状瘤向癌的恶性进展。由于TPA诱导的炎症反应常被用作皮肤肿瘤促进的标志物，我们评估了GSPs对TPA诱导炎症生物标志物的影响。免疫组织化学分析和蛋白质印迹显示，GSPs在DMBA引发/TPA促进的小鼠皮肤和皮肤肿瘤中均显著抑制环氧化酶 - 2（COX - 2）、前列腺素E(2)（PGE(2)）和增殖标志物（增殖细胞核抗原和细胞周期蛋白D1）的表达。在小鼠皮肤用急性或多次TPA处理的短期实验中，我们发现膳食GSPs抑制小鼠皮肤中TPA诱导的水肿、增生、白细胞浸润、髓过氧化物酶、COX - 2表达和PGE(2)产生。还观察到GSPs对其他结构不同的皮肤肿瘤促进剂诱导的皮肤炎症具有抑制作用。总之，我们的结果表明膳食GSPs抑制小鼠皮肤中的化学致癌作用，并且GSPs对皮肤肿瘤发生的抑制作用与对肿瘤促进剂引起的炎症反应的抑制有关。
