title: α-Tocopheryl succinate pre-treatment attenuates quinone toxicity in prostate cancer PC3 cells.
abstract: 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 4h 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,
  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
  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.
authors: Dipartimento di Medicina Sperimentale, Piazzale Gambuli, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors: Ilaria
authors: I
authors: Bellezza
authors: Dipartimento di Medicina Sperimentale, Piazzale Gambuli, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors: Silvia
authors: S
authors: Grottelli
authors: Dipartimento di Medicina Sperimentale, Piazzale Gambuli, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors: Leonardo
authors: L
authors: Gatticchi
authors: Dipartimento di Medicina Sperimentale, Piazzale Gambuli, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors: Anna Lisa
authors: AL
authors: Mierla
authors: Dipartimento di Medicina Sperimentale, Piazzale Gambuli, S. Andrea delle Fratte, 06132 Perugia, Italy. Electronic address: alba.minelli@unipg.it.
authors: Alba
authors: A
authors: Minelli
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000633:toxicity*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D006873:Hydroquinones / Q000633:toxicity; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010269:Paraquat / Q000633:toxicity; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011524:Protoporphyrins / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D043823:Taxoids / Q000633:toxicity; D024502:alpha-Tocopherol / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D016227:Benzoquinones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006873:Hydroquinones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011524:Protoporphyrins; D034741:RNA, Small Interfering; D043823:Taxoids; C017803:zinc protoporphyrin; D000077143:Docetaxel; C004532:quinone; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D005978:Glutathione; D024502:alpha-Tocopherol; D010269:Paraquat; C031927:hydroquinone
keywords: Adaptive response; Detoxification; NQO1; Nrf2