title: Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death.
abstract: BACKGROUND
  The redox-silent vitamin E analog α-tocopheryl succinate (α-TOS) was found to synergistically cooperate with vitamin K3 (VK3) plus ascorbic acid (AA) in the induction of cancer cell-selective apoptosis via a caspase-independent pathway. Here we investigated the molecular mechanism(s) underlying cell death induced in prostate cancer cells by α-TOS, VK3 and AA, and the potential use of targeted drug combination in the treatment of prostate cancer.
  
  
  RESULTS
  The generation of ROS, cellular response to oxidative stress, and autophagy were investigated in PC3 prostate cancer cells by using drugs at sub-toxic doses. We evaluated whether PARP1-mediated apoptosis-inducing factor (AIF) release plays a role in apoptosis induced by the combination of the agents. Next, the effect of the combination of α-TOS, VK3 and AA on tumor growth was examined in nude mice. VK3 plus AA induced early ROS formation associated with induction of autophagy in response to oxidative stress, which was reduced by α-TOS, preventing the formation of autophagosomes. α-TOS induced mitochondrial destabilization leading to the release of AIF. Translocation of AIF from mitochondria to the nucleus, a result of the combinatorial treatment, was mediated by PARP1 activation. The inhibition of AIF as well as of PARP1 efficiently attenuated apoptosis triggered by the drug combination. Using a mouse model of prostate cancer, the combination of α-TOS, VK3 and AA was more efficient in tumor suppression than when the drugs were given separately, without deleterious side effects.
  
  
  CONCLUSIONS
  α-TOS, a mitochondria-targeting apoptotic agent, switches at sub-apoptotic doses from autophagy-dependent survival of cancer cells to their demise by promoting the induction of apoptosis. Given the grim prognosis for cancer patients, this finding is of potential clinical relevance.
authors.affiliation: Department of Molecular and Clinical Sciences, Polytechnic University of Marche, Ancona, Italy. m.tomasetti@univpm.it
authors.forename: Marco
authors.initials: M
authors.lastname: Tomasetti
authors.forename: Linda
authors.initials: L
authors.lastname: Nocchi
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
authors.forename: Jacob
authors.initials: J
authors.lastname: Goodwin
authors.forename: Maria
authors.initials: M
authors.lastname: Nguyen
authors.forename: Lanfeng
authors.initials: L
authors.lastname: Dong
authors.forename: Nicola
authors.initials: N
authors.lastname: Manzella
authors.forename: Sara
authors.initials: S
authors.lastname: Staffolani
authors.forename: Claudio
authors.initials: C
authors.lastname: Milanese
authors.forename: Beatrice
authors.initials: B
authors.lastname: Garrone
authors.forename: Renata
authors.initials: R
authors.lastname: Alleva
authors.forename: Battista
authors.initials: B
authors.lastname: Borghi
authors.forename: Lory
authors.initials: L
authors.lastname: Santarelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Guerrieri
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D008297:Male; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D013386:Succinates / Q000008:administration & dosage / Q000494:pharmacology*; D024483:Vitamin K 3 / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051033:Apoptosis Inducing Factor; D017382:Reactive Oxygen Species; D013386:Succinates; D024483:Vitamin K 3; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D001205:Ascorbic Acid