Implication of Radical Oxygen Species in Ceramide Generation, c-Jun N-Terminal Kinase Activation and Apoptosis Induced by Daunorubicin
Anthracyclines such as daunorubicin (DNR) generate radical oxygen species (ROS), which account, at least in part, for their cytotoxic effect. We observed that early ceramide generation (within 6â10 min) through neutral sphingomyelinase stimulation was inhibitable by the antioxidants N- acetylcyste...
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| Veröffentlicht in: | Molecular pharmacology 1999-11, Vol.56 (5), p.867-874 |
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| container_title | Molecular pharmacology |
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| creator | Mas, Véronique Mansat-De Bezombes, Christine Quillet-Mary, Anne Bettaieb, Ali D’orgeix, Aurélie de Thonel Laurent, Guy Jaffrézou, Jean-Pierre |
| description | Anthracyclines such as daunorubicin (DNR) generate radical oxygen species (ROS), which account, at least in part, for their
cytotoxic effect. We observed that early ceramide generation (within 6â10 min) through neutral sphingomyelinase stimulation
was inhibitable by the antioxidants N- acetylcysteine and pyrrolidine dithiocarbamate, which led to a decrease in apoptosis (>95% decrease in DNA fragmentation after
6 h). Furthermore, we observed that DNR triggers the c-Jun N-terminal kinase (JNK) and the transcription factor activated
protein-1 through an antioxidant-inhibitable mechanism. Treatment of U937 cells with cell-permeant ceramides induced both
an increase in ROS generation and JNK activation, and apoptosis, all of which were antioxidant-sensitive. In conclusion, DNR-triggered
apoptosis implicates a ceramide-mediated, ROS-dependent JNK and activated protein-1 activation. |
| doi_str_mv | 10.1124/mol.56.5.867 |
| format | Article |
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cytotoxic effect. We observed that early ceramide generation (within 6â10 min) through neutral sphingomyelinase stimulation
was inhibitable by the antioxidants N- acetylcysteine and pyrrolidine dithiocarbamate, which led to a decrease in apoptosis (>95% decrease in DNA fragmentation after
6 h). Furthermore, we observed that DNR triggers the c-Jun N-terminal kinase (JNK) and the transcription factor activated
protein-1 through an antioxidant-inhibitable mechanism. Treatment of U937 cells with cell-permeant ceramides induced both
an increase in ROS generation and JNK activation, and apoptosis, all of which were antioxidant-sensitive. In conclusion, DNR-triggered
apoptosis implicates a ceramide-mediated, ROS-dependent JNK and activated protein-1 activation.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>DOI: 10.1124/mol.56.5.867</identifier><identifier>PMID: 10531389</identifier><language>eng</language><publisher>United States: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Acetylcysteine - pharmacology ; Antineoplastic Agents - pharmacology ; Antioxidants - pharmacology ; Apoptosis ; Cellular Biology ; Ceramides - biosynthesis ; Daunorubicin - pharmacology ; Drug Interactions ; Electron Transport - drug effects ; Enzyme Activation ; Free Radical Scavengers - antagonists & inhibitors ; Free Radical Scavengers - pharmacology ; Hematology ; Human health and pathology ; Humans ; Hydrogen Peroxide - metabolism ; JNK Mitogen-Activated Protein Kinases ; Life Sciences ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitogen-Activated Protein Kinases - metabolism ; Pyrrolidines - pharmacology ; Reactive Oxygen Species - metabolism ; Sphingomyelin Phosphodiesterase - metabolism ; Thiocarbamates - pharmacology ; Transcription Factor AP-1 - metabolism ; U937 Cells</subject><ispartof>Molecular pharmacology, 1999-11, Vol.56 (5), p.867-874</ispartof><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c351t-7686e56f0f47dec62f22eb34ddbf681d289b4e688def34e4e930df41a2371ff3</citedby><cites>FETCH-LOGICAL-c351t-7686e56f0f47dec62f22eb34ddbf681d289b4e688def34e4e930df41a2371ff3</cites><orcidid>0000-0003-4079-4872 ; 0000-0002-1849-6388 ; 0000-0002-0885-6108</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10531389$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-02349158$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Mas, Véronique Mansat-De</creatorcontrib><creatorcontrib>Bezombes, Christine</creatorcontrib><creatorcontrib>Quillet-Mary, Anne</creatorcontrib><creatorcontrib>Bettaieb, Ali</creatorcontrib><creatorcontrib>D’orgeix, Aurélie de Thonel</creatorcontrib><creatorcontrib>Laurent, Guy</creatorcontrib><creatorcontrib>Jaffrézou, Jean-Pierre</creatorcontrib><title>Implication of Radical Oxygen Species in Ceramide Generation, c-Jun N-Terminal Kinase Activation and Apoptosis Induced by Daunorubicin</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>Anthracyclines such as daunorubicin (DNR) generate radical oxygen species (ROS), which account, at least in part, for their
cytotoxic effect. We observed that early ceramide generation (within 6â10 min) through neutral sphingomyelinase stimulation
was inhibitable by the antioxidants N- acetylcysteine and pyrrolidine dithiocarbamate, which led to a decrease in apoptosis (>95% decrease in DNA fragmentation after
6 h). Furthermore, we observed that DNR triggers the c-Jun N-terminal kinase (JNK) and the transcription factor activated
protein-1 through an antioxidant-inhibitable mechanism. Treatment of U937 cells with cell-permeant ceramides induced both
an increase in ROS generation and JNK activation, and apoptosis, all of which were antioxidant-sensitive. In conclusion, DNR-triggered
apoptosis implicates a ceramide-mediated, ROS-dependent JNK and activated protein-1 activation.</description><subject>Acetylcysteine - pharmacology</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antioxidants - pharmacology</subject><subject>Apoptosis</subject><subject>Cellular Biology</subject><subject>Ceramides - biosynthesis</subject><subject>Daunorubicin - pharmacology</subject><subject>Drug Interactions</subject><subject>Electron Transport - drug effects</subject><subject>Enzyme Activation</subject><subject>Free Radical Scavengers - antagonists & inhibitors</subject><subject>Free Radical Scavengers - pharmacology</subject><subject>Hematology</subject><subject>Human health and pathology</subject><subject>Humans</subject><subject>Hydrogen Peroxide - metabolism</subject><subject>JNK Mitogen-Activated Protein Kinases</subject><subject>Life Sciences</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Pyrrolidines - pharmacology</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Sphingomyelin Phosphodiesterase - metabolism</subject><subject>Thiocarbamates - pharmacology</subject><subject>Transcription Factor AP-1 - metabolism</subject><subject>U937 Cells</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkE9v0zAYxi0EYt3gxhn5wgFp6ew4dp1j1bGtrGLS1gM3y7Fft0aJHTnNoF-Az42rTMDl_aff87zSg9AHSuaUltVVF9s5F3M-l2LxCs0oL2lBKKWv0YyQUhSy5t_P0Pkw_CCEVlySt-iMEs4ok_UM_V53feuNPvgYcHT4Udu8tfjh13EHAT_1YDwM2Ae8gqQ7bwHfQsjjSXCJTfF1DPhbsYXU-ZB197kOgJfm4J8nUx0sXvaxP8TBD3gd7GjA4uaIr_UYYhobb3x4h9443Q7w_qVfoO3Nl-3qrtg83K5Xy01hGKeHYiGkAC4ccdXCghGlK0toWGVt44SktpR1U4GQ0oJjFVRQM2JdRXXJFtQ5doE-T7Z73ao--U6no4raq7vlRp1upGRVTbl8ppm9nFiT4jAkcH8FlKhT8ionr7hQXOXkM_5xwvux6cD-B09RZ-DTy2-_2__0CVS_16nTJrZxd_xn9AdzY41n</recordid><startdate>19991101</startdate><enddate>19991101</enddate><creator>Mas, Véronique Mansat-De</creator><creator>Bezombes, Christine</creator><creator>Quillet-Mary, Anne</creator><creator>Bettaieb, Ali</creator><creator>D’orgeix, Aurélie de Thonel</creator><creator>Laurent, Guy</creator><creator>Jaffrézou, Jean-Pierre</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0003-4079-4872</orcidid><orcidid>https://orcid.org/0000-0002-1849-6388</orcidid><orcidid>https://orcid.org/0000-0002-0885-6108</orcidid></search><sort><creationdate>19991101</creationdate><title>Implication of Radical Oxygen Species in Ceramide Generation, c-Jun N-Terminal Kinase Activation and Apoptosis Induced by Daunorubicin</title><author>Mas, Véronique Mansat-De ; Bezombes, Christine ; Quillet-Mary, Anne ; Bettaieb, Ali ; D’orgeix, Aurélie de Thonel ; Laurent, Guy ; Jaffrézou, Jean-Pierre</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c351t-7686e56f0f47dec62f22eb34ddbf681d289b4e688def34e4e930df41a2371ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Acetylcysteine - pharmacology</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antioxidants - pharmacology</topic><topic>Apoptosis</topic><topic>Cellular Biology</topic><topic>Ceramides - biosynthesis</topic><topic>Daunorubicin - pharmacology</topic><topic>Drug Interactions</topic><topic>Electron Transport - drug effects</topic><topic>Enzyme Activation</topic><topic>Free Radical Scavengers - antagonists & inhibitors</topic><topic>Free Radical Scavengers - pharmacology</topic><topic>Hematology</topic><topic>Human health and pathology</topic><topic>Humans</topic><topic>Hydrogen Peroxide - metabolism</topic><topic>JNK Mitogen-Activated Protein Kinases</topic><topic>Life Sciences</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - metabolism</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Pyrrolidines - pharmacology</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Sphingomyelin Phosphodiesterase - metabolism</topic><topic>Thiocarbamates - pharmacology</topic><topic>Transcription Factor AP-1 - metabolism</topic><topic>U937 Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mas, Véronique Mansat-De</creatorcontrib><creatorcontrib>Bezombes, Christine</creatorcontrib><creatorcontrib>Quillet-Mary, Anne</creatorcontrib><creatorcontrib>Bettaieb, Ali</creatorcontrib><creatorcontrib>D’orgeix, Aurélie de Thonel</creatorcontrib><creatorcontrib>Laurent, Guy</creatorcontrib><creatorcontrib>Jaffrézou, Jean-Pierre</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mas, Véronique Mansat-De</au><au>Bezombes, Christine</au><au>Quillet-Mary, Anne</au><au>Bettaieb, Ali</au><au>D’orgeix, Aurélie de Thonel</au><au>Laurent, Guy</au><au>Jaffrézou, Jean-Pierre</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Implication of Radical Oxygen Species in Ceramide Generation, c-Jun N-Terminal Kinase Activation and Apoptosis Induced by Daunorubicin</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>1999-11-01</date><risdate>1999</risdate><volume>56</volume><issue>5</issue><spage>867</spage><epage>874</epage><pages>867-874</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><abstract>Anthracyclines such as daunorubicin (DNR) generate radical oxygen species (ROS), which account, at least in part, for their
cytotoxic effect. We observed that early ceramide generation (within 6â10 min) through neutral sphingomyelinase stimulation
was inhibitable by the antioxidants N- acetylcysteine and pyrrolidine dithiocarbamate, which led to a decrease in apoptosis (>95% decrease in DNA fragmentation after
6 h). Furthermore, we observed that DNR triggers the c-Jun N-terminal kinase (JNK) and the transcription factor activated
protein-1 through an antioxidant-inhibitable mechanism. Treatment of U937 cells with cell-permeant ceramides induced both
an increase in ROS generation and JNK activation, and apoptosis, all of which were antioxidant-sensitive. In conclusion, DNR-triggered
apoptosis implicates a ceramide-mediated, ROS-dependent JNK and activated protein-1 activation.</abstract><cop>United States</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>10531389</pmid><doi>10.1124/mol.56.5.867</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0003-4079-4872</orcidid><orcidid>https://orcid.org/0000-0002-1849-6388</orcidid><orcidid>https://orcid.org/0000-0002-0885-6108</orcidid></addata></record> |
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| ispartof | Molecular pharmacology, 1999-11, Vol.56 (5), p.867-874 |
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| language | eng |
| recordid | cdi_hal_primary_oai_HAL_hal_02349158v1 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Acetylcysteine - pharmacology Antineoplastic Agents - pharmacology Antioxidants - pharmacology Apoptosis Cellular Biology Ceramides - biosynthesis Daunorubicin - pharmacology Drug Interactions Electron Transport - drug effects Enzyme Activation Free Radical Scavengers - antagonists & inhibitors Free Radical Scavengers - pharmacology Hematology Human health and pathology Humans Hydrogen Peroxide - metabolism JNK Mitogen-Activated Protein Kinases Life Sciences Mitochondria - drug effects Mitochondria - metabolism Mitogen-Activated Protein Kinases - metabolism Pyrrolidines - pharmacology Reactive Oxygen Species - metabolism Sphingomyelin Phosphodiesterase - metabolism Thiocarbamates - pharmacology Transcription Factor AP-1 - metabolism U937 Cells |
| title | Implication of Radical Oxygen Species in Ceramide Generation, c-Jun N-Terminal Kinase Activation and Apoptosis Induced by Daunorubicin |
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