Department of Chemical Biology and Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA.
Cancer Prev Res (Phila). 2011 Mar;4(3):404-13. doi: 10.1158/1940-6207.CAPR-10-0130.
In contrast to strong epidemiologic, preclinical, and secondary clinical evidence for vitamin E (tocopherols) in reducing cancer risk, large-scale clinical cancer-prevention trials of α-tocopherol have been negative. This vexing contrast helped spur substantial preclinical efforts to better understand and improve the antineoplastic activity of tocopherol through, for example, the study of different tocopherol forms. We previously showed that the γ-tocopherol-rich mixture (γ-TmT) effectively inhibited colon and lung carcinogenesis and the growth of transplanted lung-cancer cells in mice. We designed this study to determine the relative activities of different forms of tocopherol in a xenograft model, comparing the anticancer activities of δ-tocopherol with those of α- and γ-tocopherols. We subcutaneously injected human lung cancer H1299 cells into NCr nu/nu mice, which then received α-, γ-, or δ-tocopherol or γ-TmT in the diet (each at 0.17% and 0.3%) for 49 days. δ-Tocopherol inhibited tumor growth most strongly. γ-Tocopherol and γ-TmT (at 0.3%) also inhibited growth significantly, but α-tocopherol did not. δ-Tocopherol also effectively decreased oxidative DNA damage and nitrotyrosine formation and enhanced apoptosis in tumor cells; again, γ-tocopherol also was active in these regards but less so, and α-tocopherol was not. Each supplemented diet increased serum levels of its tocopherol - up to 45 μmol/L for α-tocopherol, 9.7 μmol/L for γ-tocopherol, and 1.2 μmol/L for δ-tocopherol; dietary γ- or δ-tocopherol, however, decreased serum α-tocopherol levels, and dietary α-tocopherol decreased serum levels of γ-tocopherol. Each dietary tocopherol also increased its corresponding side-chain-degradation metabolites, with concentrations of δ-tocopherol metabolites greater than γ-tocopherol and far greater than α-tocopherol metabolites in serum and tumors. This study is the first in vivo assessment of δ-tocopherol in tumorigenesis and shows that δ-tocopherol is more active than α- or γ-tocopherol in inhibiting tumor growth, possibly through trapping reactive oxygen and nitrogen species and inducing apoptosis; δ-tocopherol metabolites could contribute significantly to these results.
与大量强有力的流行病学、临床前和二级临床证据表明维生素 E（生育酚）可降低癌症风险形成鲜明对比的是，α-生育酚的大规模临床癌症预防试验结果却是阴性的。这种令人费解的对比促使人们进行了大量的临床前研究，以便通过研究不同的生育酚形式等方法，更好地了解和提高生育酚的抗肿瘤活性。我们之前曾表明，富含γ-生育酚的混合物（γ-TmT）可有效抑制结肠癌和肺癌的发生，并抑制小鼠移植肺癌细胞的生长。我们设计了这项研究，以在异种移植模型中确定不同生育酚形式的相对活性，比较 δ-生育酚与 α-生育酚和 γ-生育酚的抗癌活性。我们将人肺癌 H1299 细胞皮下注射到 NCr nu/nu 小鼠体内，然后用饮食（每种饮食含 0.17%和 0.3%）分别补充 α-、γ-或 δ-生育酚或 γ-TmT，共 49 天。δ-生育酚对肿瘤生长的抑制作用最强。γ-生育酚和 γ-TmT（0.3%）也显著抑制了肿瘤生长，但 α-生育酚则没有。δ-生育酚还能有效降低肿瘤细胞中氧化的 DNA 损伤和硝基酪氨酸的形成，并促进细胞凋亡；同样，γ-生育酚在这方面也有活性，但活性较弱，而 α-生育酚则没有。每种补充的饮食均增加了其生育酚的血清水平-最高可达 45 μmol/L 的 α-生育酚、9.7 μmol/L 的 γ-生育酚和 1.2 μmol/L 的 δ-生育酚；然而，饮食中的 γ-或 δ-生育酚降低了血清中 α-生育酚的水平，而饮食中的 α-生育酚降低了血清中 γ-生育酚的水平。每种饮食中的生育酚还增加了其相应的侧链降解代谢物，血清和肿瘤中 δ-生育酚代谢物的浓度大于 γ-生育酚，远大于 α-生育酚代谢物。这项研究首次在体内评估了 δ-生育酚在肿瘤发生中的作用，表明 δ-生育酚在抑制肿瘤生长方面比 α-或 γ-生育酚更有效，这可能是通过捕获活性氧和氮物种并诱导细胞凋亡实现的；δ-生育酚代谢物可能对这些结果有重要贡献。
