title: 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 vivo.
abstract: Alpha-tocopheryl succinate (alpha-TOS), a redox-inactive analogue of vitamin E, is a strong inducer of apoptosis, whereas alpha-tocopherol (alpha-TOH) lacks apoptogenic activity (J. Neuzil et al., FASEB J., 15: 403-415, 2001). Here we investigated the possible antineoplastic activities of alpha-TOH and alpha-TOS and further explored the potential of alpha-TOS as an antitumor agent. Using nude mice with colon cancer xenografts, we found that alpha-TOH exerted modest antitumor activity and acted by inhibiting tumor cell proliferation. In contrast, alpha-TOS showed a more profound antitumor effect, at both the level of inhibition of proliferation and induction of tumor cell apoptosis. alpha-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, alpha-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.
authors.affiliation: Institute for Prevention of Cardiovascular Diseases, Ludwig Maximilians University, Munich, 80336 Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Weber
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Ladislav
authors.initials: L
authors.lastname: Andera
authors.forename: Harald
authors.initials: H
authors.lastname: Lahm
authors.forename: Nina
authors.initials: N
authors.lastname: Gellert
authors.forename: Marc W
authors.initials: MW
authors.lastname: Fariss
authors.forename: Vladimir
authors.initials: V
authors.lastname: Korinek
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sattler
authors.forename: David S
authors.initials: DS
authors.lastname: Ucker
authors.forename: Alexei
authors.initials: A
authors.lastname: Terman
authors.forename: Andreas
authors.initials: A
authors.lastname: Schröder
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Erl
authors.forename: Ulf T
authors.initials: UT
authors.lastname: Brunk
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D020169:Caspases / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003114:Colony-Forming Units Assay; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000166:cytology; D009361:Neoplasm Invasiveness; D053221:TNF-Related Apoptosis-Inducing Ligand; D024505:Tocopherols; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D014810:Vitamin E; D020169:Caspases; D024502:alpha-Tocopherol; D024505:Tocopherols