ABSTRACT
Two naturally occurring dietary sources of vitamin E (i.e. RRR-alpha-tocopherol (alphaT) and RRR-gamma-tocopherol (gammaT)), the manufactured synthetic form of vitamin E, all-racemic-alpha-tocopherol (all-rac-alphaT), as well as a potent antitumor analog of vitamin E, RRR-alpha-tocopherol ether-linked acetic acid analog (alpha-TEA), were assessed for anticancer actions. Data showed that gammaT, all-rac-alphaT, and alpha-TEA but not alphaT or alphaT+gammaT significantly inhibited tumor burden of human MDA-MB-231 cells in nude mice. Immunohistochemical analyses of tumor tissue showed that all-rac-alphaT and alpha-TEA increased apoptosis and decreased proliferation in tumor cells while gammaT was associated with increased tumor cell apoptosis only. In vitro data showed alpha-TEA and gammaT but not all-rac-alphaT or alphaT to inhibit colony formation and induce apoptosis. Anticancer actions of alpha-TEA and gammaT involved death receptor 5 protein upregulation, Survivin protein downregulation and poly (ADP-ribose) polymerase cleavage, all of which were blocked by co-treatment with alphaT. In summary, both gammaT and alpha-TEA exhibited promising anticancer properties in vivo and in vitro, whereas all-rac-alphaT exhibited promising anticancer properties in vivo only. Importantly, alphaT not only failed to exhibit anticancer properties but it also reduced anticancer actions of gammaT in vivo and gammaT and alpha-TEA in vitro.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Tocopherols/pharmacology , alpha-Tocopherol/pharmacology , gamma-Tocopherol/pharmacology , Animals , Annexin A5/metabolism , Antineoplastic Agents/antagonists & inhibitors , Antineoplastic Agents/blood , Apoptosis/drug effects , Biomarkers , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Female , Gene Expression Regulation, Neoplastic , Humans , Isomerism , Mice , Mice, Nude , Time Factors , Tumor Burden/drug effects , Xenograft Model Antitumor Assays , alpha-Tocopherol/blood , alpha-Tocopherol/chemistry , gamma-Tocopherol/antagonists & inhibitors , gamma-Tocopherol/bloodABSTRACT
We previously showed that dietary sesame seed and its lignan inhibited gamma-tocopherol metabolism to 2,7,8-trimethyl-2(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC), a gamma-tocopherol metabolite, and markedly elevated tissue gamma-tocopherol concentration in rats. The aim of this study was to clarify the effect of dietary sesame seed on alpha-tocopherol metabolism. Vitamin E-deficient rats fed a vitamin E-free diet for 4 wk were fed a diet containing alpha-tocopherol, alpha- and gamma-tocopherol, or alpha-tocopherol with sesame seed for 7 d. Urinary excretion of 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC), a alpha-tocopherol metabolite, in rats fed alpha-tocopherol with sesame seed was inhibited (p<0.05) as compared with that in rats fed alpha-tocopherol alone, or alpha- and gamma-tocopherol. The gamma-CEHC excretion was also less (p<0.05) in rats fed alpha-tocopherol with sesame seed than that in rats fed alpha- and gamma-tocopherol. The inhibition of alpha- and gamma-CEHC excretion by sesame seed was accompanied by elevation (p<0.05) of the alpha- and gamma-tocopherol concentration in the liver. These results suggest that dietary sesame seed inhibits not only gamma-tocopherol metabolism to gamma-CEHC but also alpha-tocopherol metabolism to alpha-CEHC in rats.
