Alpha-tocopheryl succinate selectively induces apoptosis in neuroblastoma cells: potential therapy of malignancies of the nervous system?
Vitamin E (VE) analogues, epitomized by alpha-tocopheryl succinate (alpha-TOS), are potent inducers of apoptosis and anti-cancer agents. Here, we tested their effect on the highly malignant N-type neuroblastoma (Nb) cells and their differentiated, neurone-like counterparts. Nb cells were highly susceptible to several VE analogues, while differentiated Nb cells were relatively resistant to alpha-TOS. The importance of caspase-9 rather than caspase-8, as judged by specific siRNAs studies, together with the loss of the inner mitochondrial potential, suggests that alpha-TOS triggers apoptosis in Nb cells via the mitochondrial pathway. Cultured Nb cells were sensitized to alpha-TOS by pre-treatment with Bcl-2, Bcl-xL or Mcl-1 siRNAs, while the malignant cell line was more resistant to the vitamin E analogue when Bax was knocked down. In contrast, overexpression of Bcl-2 in Nb cells rendered them more resistant to alpha-TOS-induced apoptosis. The resistance of differentiated Nb cells to alpha-TOS-mediated apoptosis occurred via two modes: first, by up-regulation of the anti-apoptotic Bcl-2 family proteins and second, by accumulation of decreased levels of reactive oxygen species when challenged with alpha-TOS. We conclude that alpha-TOS is highly selective in killing malignant brain cancer cells while relatively inert toward differentiated neuronal cells, and that vitamin E analogues may be novel therapeutics for the treatment of tumours such as neuroblastomas.
Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Queensland, Australia.
Emma
E
Swettenham
Paul K
PK
Witting
Brian A
BA
Salvatore
Jiri
J
Neuzil
D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008928:Mitochondria; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D009423:Nervous System Neoplasms / Q000188:drug therapy; D009447:Neuroblastoma / Q000473:pathology / Q000503:physiopathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D024505:Tocopherols; D015854:Up-Regulation; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494826:BAX protein, human; C494811:BCL2L1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D014810:Vitamin E; D024505:Tocopherols