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

Abstract

Vitamin E (VE) analogues, epitomized by a-tocopheryl succinate (a-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 a-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 a-TOS triggers apoptosis in Nb cells via the mitochondrial pathway. Cultured Nb cells were sensitized to a-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 a-TOS-induced apoptosis. The resistance of differentiated Nb cells to a-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 a-TOS. We conclude that a-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.