Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements.
The vitamin E analog alpha-tocopheryl succinate (alpha-TOS) can induce apoptosis. We show that the proapoptotic activity of alpha-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented alpha-TOS-triggered apoptosis. More selective effectors indicated that alpha-TOS reduced PKCalpha isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCalpha inhibition in alpha-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCalpha overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of alpha-TOS-induced proapoptotic signals. Structural analogs revealed that alpha-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, alpha-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.
Neuzil
J
J
Institute for Prevention of Cardiovascular Diseases and Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany. jneuzil@klp.med.uni-muenchen.de
Weber
T
T
Schröder
A
A
Lu
M
M
Ostermann
G
G
Gellert
N
N
Mayne
G C
GC
Olejnicka
B
B
Nègre-Salvayre
A
A
Stícha
M
M
Coffey
R J
RJ
Weber
C
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019254:Genes, bcl-2; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D019169:Jurkat Cells; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051571:Protein Kinase C-alpha; D054648:Protein Phosphatase 2; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D024505:Tocopherols; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity*; D019014:fas Receptor / Q000276:immunology / Q000502:physiology
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D020319:Oligodeoxyribonucleotides, Antisense; D019014:fas Receptor; D014810:Vitamin E; C496628:PRKCA protein, human; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate; D024505:Tocopherols