δ-Tocopherol Is More Active than α- or γ-Tocopherol in Inhibiting Lung Tumorigenesis In Vivo

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 alpha-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 gamma-tocopherol-rich mixture (gamma-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 alpha xenograft model, comparing the anticancer activities of delta-tocopherol with those of alpha- and gamma-tocopherols. We subcutaneously injected human lung cancer H1299 cells into NCr nu/nu mice, which then received alpha-, gamma-, or delta-tocopherol or gamma-TmT in the diet (each at 0.17% and 0.3%) for 49 days. delta-Tocopherol inhibited tumor growth most strongly. gamma-Tocopherol and gamma-TmT (at 0.3%) also inhibited growth significantly, but alpha-tocopherol did not. delta-Tocopherol also effectively decreased oxidative DNA damage and nitrotyrosine formation and enhanced apoptosis in tumor cells; again, gamma-tocopherol also was active in these regards but less so, and alpha-tocopherol was not. Each supplemented diet increased serum levels of its tocopherol - up to 45 mu mol/L for alpha-tocopherol, 9.7 mu mol/L for gamma-tocopherol, and 1.2 mu mol/L for delta-tocopherol; dietary gamma-or delta-tocopherol, however, decreased serum alpha-tocopherol levels, and dietary alpha-tocopherol decreased serum levels of gamma-tocopherol. Each dietary tocopherol also increased its corresponding side-chain-degradation metabolites, with concentrations of delta-tocopherol metabolites greater than gamma-tocopherol and far greater than alpha-tocopherol metabolites in serum and tumors. This study is the first in vivo assessment of delta-tocopherol in tumorigenesis and shows that delta-tocopherol is more active than alpha- or gamma-tocopherol in inhibiting tumor growth, possibly through trapping reactive oxygen and nitrogen species and inducing apoptosis; delta-tocopherol metabolites could contribute significantly to these results. Cancer Prev Res; 4(3); 404-13. (C)2011 AACR.