Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death
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...
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| creator | Tomasetti, Marco Nocchi, Linda Neuzil, Jiri Goodwin, Jacob Nguyen, Maria Dong, Lanfeng Manzella, Nicola Staffolani, Sara Milanese, Claudio Garrone, Beatrice Alleva, Renata Borghi, Battista Santarelli, Lory Guerrieri, Roberto |
| description | 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.
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.
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. |
| doi_str_mv | 10.1371/journal.pone.0052263 |
| format | Article |
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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.
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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0052263</identifier><identifier>PMID: 23272231</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Anesthesiology ; Animals ; Apoptosis ; Apoptosis Inducing Factor - metabolism ; Apoptosis-inducing factor ; Ascorbic acid ; Ascorbic Acid - administration & dosage ; Ascorbic Acid - pharmacology ; Autophagy ; Autophagy - drug effects ; Biochemistry ; Biology ; Cancer ; Cancer cells ; Cancer therapies ; Caspase ; Caspases - metabolism ; Cell death ; Cell Line, Tumor ; Cell survival ; Combination drug therapy ; Combinatorial analysis ; Deoxyribonucleic acid ; Destabilization ; Disease Progression ; DNA ; Drug dosages ; Drugs ; Enzymes ; Humans ; Investigations ; Male ; Medicine ; Mice ; Mitochondria ; Organic acids ; Oxidative stress ; Phagocytosis ; Phagosomes ; Poly(ADP-ribose) polymerase ; Poly(ADP-ribose) Polymerases - metabolism ; Prostate cancer ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - metabolism ; Protein Transport ; Reactive Oxygen Species - metabolism ; Science ; Side effects ; Succinates - administration & dosage ; Succinates - pharmacology ; Survival ; Switches ; Tocopherol ; Translocation ; Tumor suppression ; Vitamin E ; Vitamin K 3 - administration & dosage ; Vitamin K 3 - pharmacology ; Xenograft Model Antitumor Assays</subject><ispartof>PloS one, 2012-12, Vol.7 (12), p.e52263</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Tomasetti et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012 Tomasetti et al 2012 Tomasetti et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-dc19d06eb2fd34fdb22014e4f53329d65a5b22b3bfe5b348b21c48c72e5d392f3</citedby><cites>FETCH-LOGICAL-c692t-dc19d06eb2fd34fdb22014e4f53329d65a5b22b3bfe5b348b21c48c72e5d392f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525640/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525640/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23272231$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tomasetti, Marco</creatorcontrib><creatorcontrib>Nocchi, Linda</creatorcontrib><creatorcontrib>Neuzil, Jiri</creatorcontrib><creatorcontrib>Goodwin, Jacob</creatorcontrib><creatorcontrib>Nguyen, Maria</creatorcontrib><creatorcontrib>Dong, Lanfeng</creatorcontrib><creatorcontrib>Manzella, Nicola</creatorcontrib><creatorcontrib>Staffolani, Sara</creatorcontrib><creatorcontrib>Milanese, Claudio</creatorcontrib><creatorcontrib>Garrone, Beatrice</creatorcontrib><creatorcontrib>Alleva, Renata</creatorcontrib><creatorcontrib>Borghi, Battista</creatorcontrib><creatorcontrib>Santarelli, Lory</creatorcontrib><creatorcontrib>Guerrieri, Roberto</creatorcontrib><title>Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.
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.
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.</description><subject>Analysis</subject><subject>Anesthesiology</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis Inducing Factor - metabolism</subject><subject>Apoptosis-inducing factor</subject><subject>Ascorbic acid</subject><subject>Ascorbic Acid - administration & dosage</subject><subject>Ascorbic Acid - pharmacology</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Biochemistry</subject><subject>Biology</subject><subject>Cancer</subject><subject>Cancer cells</subject><subject>Cancer therapies</subject><subject>Caspase</subject><subject>Caspases - metabolism</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Cell survival</subject><subject>Combination drug therapy</subject><subject>Combinatorial analysis</subject><subject>Deoxyribonucleic acid</subject><subject>Destabilization</subject><subject>Disease Progression</subject><subject>DNA</subject><subject>Drug dosages</subject><subject>Drugs</subject><subject>Enzymes</subject><subject>Humans</subject><subject>Investigations</subject><subject>Male</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mitochondria</subject><subject>Organic acids</subject><subject>Oxidative stress</subject><subject>Phagocytosis</subject><subject>Phagosomes</subject><subject>Poly(ADP-ribose) polymerase</subject><subject>Poly(ADP-ribose) Polymerases - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tomasetti, Marco</au><au>Nocchi, Linda</au><au>Neuzil, Jiri</au><au>Goodwin, Jacob</au><au>Nguyen, Maria</au><au>Dong, Lanfeng</au><au>Manzella, Nicola</au><au>Staffolani, Sara</au><au>Milanese, Claudio</au><au>Garrone, Beatrice</au><au>Alleva, Renata</au><au>Borghi, Battista</au><au>Santarelli, Lory</au><au>Guerrieri, Roberto</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-12-18</date><risdate>2012</risdate><volume>7</volume><issue>12</issue><spage>e52263</spage><pages>e52263-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.
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.
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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23272231</pmid><doi>10.1371/journal.pone.0052263</doi><tpages>e52263</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-12, Vol.7 (12), p.e52263 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1327199424 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Analysis Anesthesiology Animals Apoptosis Apoptosis Inducing Factor - metabolism Apoptosis-inducing factor Ascorbic acid Ascorbic Acid - administration & dosage Ascorbic Acid - pharmacology Autophagy Autophagy - drug effects Biochemistry Biology Cancer Cancer cells Cancer therapies Caspase Caspases - metabolism Cell death Cell Line, Tumor Cell survival Combination drug therapy Combinatorial analysis Deoxyribonucleic acid Destabilization Disease Progression DNA Drug dosages Drugs Enzymes Humans Investigations Male Medicine Mice Mitochondria Organic acids Oxidative stress Phagocytosis Phagosomes Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerases - metabolism Prostate cancer Prostatic Neoplasms - genetics Prostatic Neoplasms - metabolism Protein Transport Reactive Oxygen Species - metabolism Science Side effects Succinates - administration & dosage Succinates - pharmacology Survival Switches Tocopherol Translocation Tumor suppression Vitamin E Vitamin K 3 - administration & dosage Vitamin K 3 - pharmacology Xenograft Model Antitumor Assays |
| title | Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death |
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