Alpha-Tocopheryl Succinate Inhibits Autophagic Survival of Prostate Cancer Cells Induced by Vitamin K3 and Ascorbate to Trigger Cell Death

作者：Tomasetti Marco^*; Nocchi Linda; Neuzil Jiri; Goodwin Jacob; Maria Nguyen; Dong Lanfeng; Manzella Nicola; Staffolani Sara; Milanese Claudio; Garrone Beatrice; Alleva Renata; Borghi Battista; Santarelli Lory; Guerrieri Roberto

来源：PLos One, 2012, 7(12): e52263.

DOI：10.1371/journal.pone.0052263

Background: The redox-silent vitamin E analog alpha-tocopheryl succinate (alpha-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 alpha-TOS, VK3 and AA, and the potential use of targeted drug combination in the treatment of prostate cancer. %26lt;br%26gt;Methodology/Principal Findings: 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 alpha-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 alpha-TOS, preventing the formation of autophagosomes. alpha-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 alpha-TOS, VK3 and AA was more efficient in tumor suppression than when the drugs were given separately, without deleterious side effects. %26lt;br%26gt;Conclusions/Significance: alpha-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.

• 出版日期2012-12-18