chemical inhibitor of Apaf-1 exerts mitochondrioprotective functions and interferes with the intra-S-phase DNA damage checkpoint
QM31 represents a new class of cytoprotective agents that inhibit the formation of the apoptosome, the caspase activation complex composed by Apaf-1, cytochrome c, dATP and caspase-9. Here, we analyzed the cellular effects of QM31, as compared to the prototypic caspase inhibitor Z-VAD-fmk. QM31 was...
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| Veröffentlicht in: | Apoptosis (London) 2009-02, Vol.14 (2), p.182-190 |
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| creator | Mondragón, Laura Galluzzi, Lorenzo Mouhamad, Shahul Orzáez, Mar Vicencio, José-Miguel Vitale, Ilio Moure, Alejandra Messeguer, Angel Perez-Paya, Enrique Kroemer, Guido |
| description | QM31 represents a new class of cytoprotective agents that inhibit the formation of the apoptosome, the caspase activation complex composed by Apaf-1, cytochrome c, dATP and caspase-9. Here, we analyzed the cellular effects of QM31, as compared to the prototypic caspase inhibitor Z-VAD-fmk. QM31 was as efficient as Z-VAD-fmk in suppressing caspase-3 activation, and conferred a similar cytoprotective effect. In contrast to Z-VAD-fmk, QM31 inhibited the release of cytochrome c from mitochondria, an unforeseen property that may contribute to its pronounced cytoprotective activity. Moreover, QM31 suppressed the Apaf-1-dependent intra-S-phase DNA damage checkpoint. These results suggest that QM31 can interfere with the two known functions of Apaf-1, namely apoptosome assembly/activation and intra-S-phase cell cycle arrest. Moreover, QM31 can inhibit mitochondrial outer membrane permeabilization, an effect that is independent from its action on Apaf-1. |
| doi_str_mv | 10.1007/s10495-008-0310-x |
| format | Article |
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Moreover, QM31 can inhibit mitochondrial outer membrane permeabilization, an effect that is independent from its action on Apaf-1.</description><identifier>ISSN: 1360-8185</identifier><identifier>EISSN: 1573-675X</identifier><identifier>DOI: 10.1007/s10495-008-0310-x</identifier><identifier>PMID: 19152031</identifier><language>eng</language><publisher>Boston: Boston : Springer US</publisher><subject>Amino Acid Chloromethyl Ketones - pharmacology ; Apoptotic Protease-Activating Factor 1 - antagonists & inhibitors ; Apoptotic Protease-Activating Factor 1 - deficiency ; Azepines - pharmacology ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Carcinoma, Non-Small-Cell Lung - pathology ; Cell Biology ; Cell Line, Tumor ; Cell Membrane Permeability - drug effects ; Cytochrome ; Deoxyribonucleic acid ; DNA ; DNA Damage ; Fluorescent Antibody Technique ; Humans ; Lung Neoplasms - pathology ; Mitochondria - drug effects ; Oncology ; Original Paper ; Peptoids - pharmacology ; RNA, Small Interfering - metabolism ; S Phase - drug effects ; Transfection ; Virology</subject><ispartof>Apoptosis (London), 2009-02, Vol.14 (2), p.182-190</ispartof><rights>Springer Science+Business Media, LLC 2009</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c393t-1be1e453611300430e519b06a149aca37b4e0345e89a6464d4617bb16523ada03</citedby><cites>FETCH-LOGICAL-c393t-1be1e453611300430e519b06a149aca37b4e0345e89a6464d4617bb16523ada03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10495-008-0310-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10495-008-0310-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19152031$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mondragón, Laura</creatorcontrib><creatorcontrib>Galluzzi, Lorenzo</creatorcontrib><creatorcontrib>Mouhamad, Shahul</creatorcontrib><creatorcontrib>Orzáez, Mar</creatorcontrib><creatorcontrib>Vicencio, José-Miguel</creatorcontrib><creatorcontrib>Vitale, Ilio</creatorcontrib><creatorcontrib>Moure, Alejandra</creatorcontrib><creatorcontrib>Messeguer, Angel</creatorcontrib><creatorcontrib>Perez-Paya, Enrique</creatorcontrib><creatorcontrib>Kroemer, Guido</creatorcontrib><title>chemical inhibitor of Apaf-1 exerts mitochondrioprotective functions and interferes with the intra-S-phase DNA damage checkpoint</title><title>Apoptosis (London)</title><addtitle>Apoptosis</addtitle><addtitle>Apoptosis</addtitle><description>QM31 represents a new class of cytoprotective agents that inhibit the formation of the apoptosome, the caspase activation complex composed by Apaf-1, cytochrome c, dATP and caspase-9. 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Moreover, QM31 can inhibit mitochondrial outer membrane permeabilization, an effect that is independent from its action on Apaf-1.</description><subject>Amino Acid Chloromethyl Ketones - pharmacology</subject><subject>Apoptotic Protease-Activating Factor 1 - antagonists & inhibitors</subject><subject>Apoptotic Protease-Activating Factor 1 - deficiency</subject><subject>Azepines - pharmacology</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell Membrane Permeability - drug effects</subject><subject>Cytochrome</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Damage</subject><subject>Fluorescent Antibody Technique</subject><subject>Humans</subject><subject>Lung Neoplasms - pathology</subject><subject>Mitochondria - drug effects</subject><subject>Oncology</subject><subject>Original Paper</subject><subject>Peptoids - 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Here, we analyzed the cellular effects of QM31, as compared to the prototypic caspase inhibitor Z-VAD-fmk. QM31 was as efficient as Z-VAD-fmk in suppressing caspase-3 activation, and conferred a similar cytoprotective effect. In contrast to Z-VAD-fmk, QM31 inhibited the release of cytochrome c from mitochondria, an unforeseen property that may contribute to its pronounced cytoprotective activity. Moreover, QM31 suppressed the Apaf-1-dependent intra-S-phase DNA damage checkpoint. These results suggest that QM31 can interfere with the two known functions of Apaf-1, namely apoptosome assembly/activation and intra-S-phase cell cycle arrest. Moreover, QM31 can inhibit mitochondrial outer membrane permeabilization, an effect that is independent from its action on Apaf-1.</abstract><cop>Boston</cop><pub>Boston : Springer US</pub><pmid>19152031</pmid><doi>10.1007/s10495-008-0310-x</doi><tpages>9</tpages></addata></record> |
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| subjects | Amino Acid Chloromethyl Ketones - pharmacology Apoptotic Protease-Activating Factor 1 - antagonists & inhibitors Apoptotic Protease-Activating Factor 1 - deficiency Azepines - pharmacology Biochemistry Biomedical and Life Sciences Biomedicine Cancer Research Carcinoma, Non-Small-Cell Lung - pathology Cell Biology Cell Line, Tumor Cell Membrane Permeability - drug effects Cytochrome Deoxyribonucleic acid DNA DNA Damage Fluorescent Antibody Technique Humans Lung Neoplasms - pathology Mitochondria - drug effects Oncology Original Paper Peptoids - pharmacology RNA, Small Interfering - metabolism S Phase - drug effects Transfection Virology |
| title | chemical inhibitor of Apaf-1 exerts mitochondrioprotective functions and interferes with the intra-S-phase DNA damage checkpoint |
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