Jang M, Pezzuto J M
Department of Surgical Oncology, University of Illinois at Chicago, USA.
Drugs Exp Clin Res. 1999;25(2-3):65-77.
Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a naturally occurring compound shown to inhibit carcinogen-induced preneoplastic lesion formation in mouse mammary organ culture and tumorigenesis in the two-stage mouse skin model. Cancer chemopreventive potential was also suggested in various assays reflective of the three major stages of carcinogenesis. Anti-initiation activity was indicated by its antioxidant and antimutagenic effects, inhibition of the hydroperoxidase function of cyclooxygenase (COX), and induction of phase II drug-metabolizing enzymes. Antipromotion activity was indicated by antiinflammatory effects, inhibition of production of arachidonic acid metabolites catalyzed by either COX-1 or COX-2, and chemical carcinogen-induced neoplastic transformation of mouse embryo fibroblasts. Antiprogression activity was demonstrated by its ability to induce human promyelocytic leukemia (HL-60) cell differentiation. Moreover, pretreatment of mouse skin with resveratrol significantly counteracted 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative stress, as evidenced by numerous biochemical responses. Resveratrol reduced the generation of hydrogen peroxide, and normalized levels of myeloperoxidase and oxidized-glutathione reductase activities. It also restored glutathione levels and superoxide dismutase activity. As judged by the reverse transcriptase-polymerase chain reaction, resveratrol selectively inhibited TPA-induced expression of c-fos and transforming growth factor-beta 1 (TGF-beta 1), but did not affect other TPA-induced gene products including COX-1, COX-2, c-myc, c-jun, and tumor necrosis factor-alpha. These data indicate that resveratrol may interfere with reactive oxidant pathways and/or modulate the expression of c-fos and TGF-beta 1 to inhibit tumorigenesis in mouse skin. As reported herein, in addition to the activities described above, resveratrol inhibited the de novo formation of inducible nitric oxide synthase (iNOS) in mouse macrophages stimulated with lipopolysaccharide. This finding suggests an additional mechanism by which resveratrol may function as a cancer chemopreventive agent.
白藜芦醇（3,5,4'-三羟基反式芪）是一种天然存在的化合物，已证明其可抑制致癌物诱导的小鼠乳腺器官培养中的癌前病变形成以及两阶段小鼠皮肤模型中的肿瘤发生。在反映致癌作用三个主要阶段的各种试验中，也显示出其具有癌症化学预防潜力。其抗氧化和抗诱变作用、对环氧合酶（COX）氢过氧化物酶功能的抑制以及II期药物代谢酶的诱导表明了其抗启动活性。抗炎作用、对COX-1或COX-2催化的花生四烯酸代谢产物生成的抑制以及化学致癌物诱导的小鼠胚胎成纤维细胞的肿瘤转化表明了其抗促进活性。其诱导人早幼粒细胞白血病（HL-60）细胞分化的能力证明了其抗进展活性。此外，用白藜芦醇预处理小鼠皮肤可显著抵消12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的氧化应激，众多生化反应证明了这一点。白藜芦醇减少了过氧化氢的生成，并使髓过氧化物酶和氧化型谷胱甘肽还原酶活性水平恢复正常。它还恢复了谷胱甘肽水平和超氧化物歧化酶活性。通过逆转录酶-聚合酶链反应判断，白藜芦醇选择性抑制TPA诱导的c-fos和转化生长因子-β1（TGF-β1）的表达，但不影响其他TPA诱导的基因产物，包括COX-1、COX-2、c-myc、c-jun和肿瘤坏死因子-α。这些数据表明，白藜芦醇可能干扰活性氧化途径和/或调节c-fos和TGF-β1的表达以抑制小鼠皮肤肿瘤发生。如本文所报道，除上述活性外，白藜芦醇还抑制脂多糖刺激的小鼠巨噬细胞中诱导型一氧化氮合酶（iNOS）的从头形成。这一发现提示了白藜芦醇作为癌症化学预防剂可能发挥作用的另一种机制。
