Cancer chemopreventive activity of resveratrol
Cancer chemopreventive activity of resveratrol
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DOI：
10.1111/j.1749-6632.2002.tb02918.x
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发表时间：
2002-01-01
期刊：
影响因子：
--
通讯作者：
Pezzuto, JM
中科院分区：
文献类型：
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作者：
Bhat, KPL;Pezzuto, JM
癌症化学预防剂旨在通过干预癌发生的一个或多个阶段来降低肿瘤发生的发生率。最近，人类饮食中发现的天然产物白藜芦醇被证明具有癌症化学预防剂的作用。白藜芦醇首先被证明可作为抗氧化剂和抗诱变剂，从而作为抗引发剂。进一步的证据表明，在小鼠乳腺器官培养模型中，白藜芦醇选择性抑制细胞色素P-450 I A I的转录激活，并抑制致癌物诱导的癌前病变的形成。在两阶段模型中，白藜芦醇还可抑制 12-O-十四烷酰佛波醇-13-乙酸酯 (TPA) 促进的小鼠皮肤肿瘤的形成。在无细胞模型中，白藜芦醇抑制 COX-1 和 -2 的酶活性，在乳腺上皮细胞中，白藜芦醇抑制 COX-2 mRNA 和 TPA 诱导的蛋白激酶 C 激活以及 AP-1 介导的基因表达。此外，白藜芦醇强烈抑制一氧化氮的生成和诱导型一氧化氮合酶蛋白的表达。 NFkappaB 与炎症和免疫反应密切相关，并与某些癌症模型中的肿瘤发生相关，而白藜芦醇可通过多种药物抑制该转录因子的诱导。其机制可能涉及减少 IkappaBalpha 的磷酸化和降解。在细胞水平上，白藜芦醇还可诱导细胞凋亡、细胞周期延迟或许多细胞系中 G(1) --> S 过渡期的阻断。因此，白藜芦醇作为化学预防剂在未来的发展中具有广阔的前景，可用于治疗多种疾病。临床前毒性研究正在进行中，随后应进行人体临床试验。
Cancer chemopreventive agents are designed to reduce the incidence of tumorigenesis by intervening at one or more stages of carcinogenesis. Recently, resveratrol, a natural product found in the diet of humans, hits been shown to function as a cancer chemopreventive agent. Resveratrol was first shown to act as an antioxidant and antimutagenic agent, thus acting as an anti-initiation agent. Further evidence indicated that resveratrol selectively suppresses the transcriptional activation Of Cytochrome P-450 I A I and inhibits the formation of carcinogen-induced preneoplastic lesions in a mouse mammary organ culture model. Resveratrol also inhibits the formation of 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted mouse skin tumors in the two-stage model. The enzymatic activities of COX-1 and -2 are inhibited by resveratrol in cell-free models, and COX-2 mRNA and TPA-induced activation of protein kinase C and AP-1-mediated gene expression are suppressed by resveratrol in mammary epithelial cells. In addition, resveratrol strongly inhibits nitric oxide generation and inducible nitric oxide synthase protein expression. NFkappaB is strongly linked to inflammatory and immune responses and is associated with oncogenesis in certain models of cancer, and resveratrol suppresses the induction of this transcription factor by a number of agents. The mechanism may involve decreasing the phosphorylation and degradation of IkappaBalpha. At the cellular level, resveratrol also induces apoptosis, cell cycle delay or a block in the G(1) --> S transition phase in a number of cell lines, Thus, resveratrol holds great promise for future development as a chemopreventive agent that may be useful for several disorders. Preclinical toxicity studies are underway that should be followed by human clinical trials.