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-tocopheryl succinate: molecular pathways and structural requirements
* Institute for Prevention of Cardiovascular Diseases and Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany;
Medical Center North, Vanderbilt University, Nashville, Tennessee, USA;
Flinders University of South Australia, Adelaide, South Australia, Australia;
§ Department of Pathology II, University Hospital, Linköping, Sweden;
¶ Biochemistry Department, INSERM, Toulouse, France; and
Faculty of Science, Charles University, Prague, Czech Republic
1Correspondence: Institute for Prevention of Cardiovascular Diseases, Pettenkoferstrasse 9, 80336 Munich, Germany. E-mail: jneuzil{at}klp.med.uni-muenchen.de or cweber{at}klp.med.uni-muenchen.de
The vitamin E analog 
-tocopheryl succinate (-TOS) can induce
apoptosis. We show that the proapoptotic activity of -TOS in
hematopoietic and cancer cell lines involves inhibition of protein
kinase C (PKC), since phorbol myristyl acetate prevented
-TOS-triggered apoptosis. More selective effectors indicated that
-TOS reduced PKC isotype activity by increasing protein
phosphatase 2A (PP2A) activity. The role of PKC inhibition in
-TOS-induced apoptosis was confirmed using antisense
oligonucleotides or PKC overexpression. Gain- or loss-of-function
bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a
mitochondrial target of -TOS-induced proapoptotic signals.
Structural analogs revealed that -tocopheryl and succinyl moieties
are both required for maximizing these effects. In mice with colon
cancer xenografts, -TOS suppressed tumor growth by 80%. This
epitomizes cancer cell killing by a pharmacologically relevant compound
without known side effects.—Neuzil, J., Weber, T., Schröder, A.,
Lu, M., Ostermann, G., Gellert, N., Mayne, G. C., Olejnicka, B.,
Nègre-Salvayre, A., Stícha, M., Coffey, R. J.,
Weber, C. Induction of cancer cell apoptosis by -tocopheryl
succinate: molecular pathways and structural requirements.
Key Words: vitamin E succinate • protein kinase C • programmed cell death • colon cancer
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