α‐Tocopheryl succinate selectively induces apoptosis in neuroblastoma cells: potential therapy of malignancies of the nervous system?

Vitamin E (VE) analogues, epitomized by α‐tocopheryl succinate (α‐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 α‐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 α‐TOS triggers apoptosis in Nb cells via the mitochondrial pathway. Cultured Nb cells were sensitized to α‐TOS by pre‐treatment with Bcl‐2, Bcl‐x L 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 α‐TOS‐induced apoptosis. The resistance of differentiated Nb cells to α‐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 α‐TOS. We conclude that α‐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.