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Vitamin E Succinate Is a Potent Novel Antineoplastic Agent with High Selectivity and Cooperativity with Tumor Necrosis Factor-related Apoptosis-inducing Ligand (Apo2 Ligand) in Vivo¹

Institute for Prevention of Cardiovascular Diseases, Ludwig Maximilians University, Munich, 80336 Germany [T. W., N. G., A. S., W. E., C. W., J. N.]; Division of Pathology II, University Hospital, Linköping SE-581 85, Sweden [A. T., U. T. B., J. N.]; Department of Medicine and Cell Biology, Vanderbilt University, Nashville, Tennessee 37235 [M. L., R. J. C.]; Institute of Molecular Genetics, Czech Academy of Sciences, Prague, 14220 Czech Republic [L. A., V. K.]; Institute of Molecular Animal Breeding, Ludwig Maximilians University, Munich, 81377 Germany [H. L.]; Department of Pharmaceutical Sciences, Washington State University, Pullman, Washington 99164 [M. W. F.]; Institute of Medical Biochemistry, University of Graz, 8010 Graz, Austria [W. S.]; Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois 60612 [D. S. U.]; and Department of Cardiovascular Molecular Biology, University Hospital, Aachen, 52057 Germany [C. W.]

-Tocopheryl succinate (-TOS), a redox-inactive analogue of vitamin E, is a strong inducer of apoptosis, whereas -tocopherol (-TOH) lacks apoptogenic activity (J. Neuzil et al., FASEB J., 15: 403–415, 2001). Here we investigated the possible antineoplastic activities of -TOH and -TOS and further explored the potential of -TOS as an antitumor agent. Using nude mice with colon cancer xenografts, we found that -TOH exerted modest antitumor activity and acted by inhibiting tumor cell proliferation. In contrast, -TOS showed a more profound antitumor effect, at both the level of inhibition of proliferation and induction of tumor cell apoptosis. -TOS was nontoxic to normal cells and tissues, triggered apoptosis in p53^-/- and p21^{Waf1/Cip1(-/-)} cancer cells, and exerted a cooperative proapoptotic activity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) due to differences in proapoptotic signaling. Finally, -TOS cooperated with tumor necrosis factor-related apoptosis-inducing ligand in suppression of tumor growth in vivo. Vitamin E succinate is thus a potent and highly specific anticancer agent and/or adjuvant of considerable therapeutic potential.

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