α-Tocopheryl succinate pre-treatment attenuates quinone toxicity in prostate cancer PC3 cells

- α-tocopheryl succinate pre-treatment increases intracellular GSH.
- α-tocopheryl succinate pre-treatment decreases quinone toxicity.
- Inhibition of NQO1 activity counteracts α-tocopheryl succinate-induced adaptive response

α-Tocopheryl succinate is one of the most effective analogues of vitamin E for inhibiting cell proliferation and inducing cell death in a variety of cancerous cell lines while sparing normal cells or tissues. αTocopheryl succinate inhibits oxidative phosphorylation at the level of mitochondrial complexes I and II, thus enhancing reactive oxygen species generation which, in turn, induces the expression of Nrf2-driven antioxidant/detoxifying genes. The cytoprotective role of Nrf2 downstream genes/proteins prompted us to investigate whether and how α-tocopheryl succinate increases resistance of PC3 prostate cancer cells to pro-oxidant damage. A 4 h α-tocopheryl succinate pre-treatment increases glutathione intracellular content, indicating that the vitamin E derivative is capable of training the cells to react to an oxidative insult. We found that α-tocopheryl succinate pre-treatment does not enhance paraquat-/hydroquinone-induced cytotoxicity whereas it exhibits an additional/synergistic effect on H2O2-/docetaxel-induced cytotoxicity.While glutathione and heme oxygenase-1 are not involved in α-tocopheryl succinate-induced adaptive response to paraquat, NAD(P)H:quinone oxidoreductase seems to be responsible, at least in part, for the lack of the additional response. Silencing the gene and/or the inhibition of NAD(P)H:quinone oxidoreductase activity counteracts the α-tocopheryl succinate-induced adaptive response. In conclusion, the adaptive response to α-tocopheryl succinate shows that the activation of Nrf2 can promote the survival of cancer cells in an unfavourable environment.