Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death.

<h4>Background</h4>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 molecul...

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Autores principales: Marco Tomasetti, Linda Nocchi, Jiri Neuzil, Jacob Goodwin, Maria Nguyen, Lanfeng Dong, Nicola Manzella, Sara Staffolani, Claudio Milanese, Beatrice Garrone, Renata Alleva, Battista Borghi, Lory Santarelli, Roberto Guerrieri
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Publicado: Public Library of Science (PLoS) 2012
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spelling oai:doaj.org-article:a4582d3a4c6c4292a996162359869d532021-11-18T08:04:38ZAlpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death.1932-620310.1371/journal.pone.0052263https://doaj.org/article/a4582d3a4c6c4292a996162359869d532012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23272231/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.Marco TomasettiLinda NocchiJiri NeuzilJacob GoodwinMaria NguyenLanfeng DongNicola ManzellaSara StaffolaniClaudio MilaneseBeatrice GarroneRenata AllevaBattista BorghiLory SantarelliRoberto GuerrieriPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 12, p e52263 (2012)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Marco Tomasetti
Linda Nocchi
Jiri Neuzil
Jacob Goodwin
Maria Nguyen
Lanfeng Dong
Nicola Manzella
Sara Staffolani
Claudio Milanese
Beatrice Garrone
Renata Alleva
Battista Borghi
Lory Santarelli
Roberto Guerrieri
Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death.
description <h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.
format article
author Marco Tomasetti
Linda Nocchi
Jiri Neuzil
Jacob Goodwin
Maria Nguyen
Lanfeng Dong
Nicola Manzella
Sara Staffolani
Claudio Milanese
Beatrice Garrone
Renata Alleva
Battista Borghi
Lory Santarelli
Roberto Guerrieri
author_facet Marco Tomasetti
Linda Nocchi
Jiri Neuzil
Jacob Goodwin
Maria Nguyen
Lanfeng Dong
Nicola Manzella
Sara Staffolani
Claudio Milanese
Beatrice Garrone
Renata Alleva
Battista Borghi
Lory Santarelli
Roberto Guerrieri
author_sort Marco Tomasetti
title Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death.
title_short Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death.
title_full Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death.
title_fullStr Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death.
title_full_unstemmed Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death.
title_sort alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin k3 and ascorbate to trigger cell death.
publisher Public Library of Science (PLoS)
publishDate 2012
url https://doaj.org/article/a4582d3a4c6c4292a996162359869d53
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