Dietary grape seed proanthocyanidins inhibit 12-O-tetradecanoyl phorbol-13-acetate-caused skin tumor promotion in 7,12-dimethylbenz[a]anthracene-initiated mouse skin, which is associated with the inhibition of inflammatory responses
Dietary grape seed proanthocyanidins inhibit 12-O-tetradecanoyl phorbol-13-acetate-caused skin tumor promotion in 7,12-dimethylbenz[a]anthracene-initiated mouse skin, which is associated with the inhibition of inflammatory responses
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DOI：
10.1093/carcin/bgp019
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发表时间：
2009-03-01
期刊：
影响因子：
4.7
通讯作者：
Katiyar, Santosh K.
中科院分区：
文献类型：
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作者：
Meeran, Syed M.;Vaid, Mudit;Katiyar, Santosh K.
葡萄籽原花青素（GSP）具有抗癌活性。在这里，我们评估了膳食 GSP 对 7,12-二甲基苯并[a]蒽 (DMBA) 引发的小鼠皮肤中 12-O-十四烷酰佛波醇-13-乙酸酯 (TPA) 诱导的皮肤肿瘤促进的影响。给予对照 AIN76A 饮食补充的膳食 GSP（0.2 和 0.5%，wt/wt）可显着抑制 C3H/HeN 小鼠中 TPA 诱导的皮肤肿瘤促进。与接受对照饮食的小鼠相比，接受 GSP 治疗的小鼠的肿瘤负荷显着降低，包括肿瘤小鼠百分比 (P < 0.05)、每组肿瘤总数 (P < 0.01，n = 20) 和每只荷瘤小鼠的总肿瘤体积 (P < 0.01-0.001)。 GSP 还延缓了乳头状瘤向癌的恶性进展。由于 TPA 诱导的炎症反应通常用作皮肤肿瘤促进的标志物，因此我们评估了 GSP 对 TPA 诱导的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，GSP 显着抑制 DMBA 启动/TPA 促进的小鼠皮肤和皮肤肿瘤中环氧合酶 2 (COX-2)、前列腺素 E-2 (PGE(2)) 和增殖标记物（增殖细胞核抗原和细胞周期蛋白 D1）的表达。在对小鼠皮肤进行急性或多次TPA处理的短期实验中，我们发现膳食GSP可抑制TPA诱导的小鼠皮肤水肿、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 GSP 对其他结构不同的皮肤肿瘤启动子诱导的皮肤炎症的抑制作用。总之，我们的结果表明，膳食 GSP 可抑制小鼠皮肤的化学致癌作用，并且 GSP 对皮肤肿瘤发生的抑制与对肿瘤促进剂引起的炎症反应的抑制有关。
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.