Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells
One of the mechanisms of action of a new oncolytic agent, benzamide riboside (BR) is by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH) which catalyzes the formation of xanthine 5'-monophosphate from inosine 5'-monophosphate and nicotinamide adenine dinucleotide, thereby res...
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Veröffentlicht in: | Cell death and differentiation 1999-08, Vol.6 (8), p.736-744 |
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creator | Grusch, M Rosenberger, G Fuhrmann, G Braun, K Titscher, B Szekeres, T Fritzer-Skekeres, M Oberhuber, G Krohn, K Hengstschlaeger, M Krupitza, G Jayaram, H N |
description | One of the mechanisms of action of a new oncolytic agent, benzamide riboside (BR) is by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH) which catalyzes the formation of xanthine 5'-monophosphate from inosine 5'-monophosphate and nicotinamide adenine dinucleotide, thereby restricting the biosynthesis of guanylates. In the present study BR (10 - 20 microM) induced apoptosis in a human ovarian carcinoma N.1 cell line (a monoclonal derivative of its heterogenous parent line HOC-7). This was ascertained by DNA fragmentation, TUNEL assay, [poly(ADP)ribose polymerase]-cleavage and alteration in cell morphology. Apoptosis was accompanied by sustained c-Myc expression, concurrent down-regulation of cdc25A mRNA and protein, and by inhibition of Cdk2 activity. Both Cdk2 and cdc25A are G1 phase specific genes and Cdk2 is the target of Cdc25A. These studies demonstrate that BR exhibits dual mechanisms of action, first by inhibiting IMPDH, and second by inducing apoptosis, which is associated with repression of components of the cell cycle that are downstream of constitutive c-Myc expression. |
doi_str_mv | 10.1038/sj.cdd.4400546 |
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In the present study BR (10 - 20 microM) induced apoptosis in a human ovarian carcinoma N.1 cell line (a monoclonal derivative of its heterogenous parent line HOC-7). This was ascertained by DNA fragmentation, TUNEL assay, [poly(ADP)ribose polymerase]-cleavage and alteration in cell morphology. Apoptosis was accompanied by sustained c-Myc expression, concurrent down-regulation of cdc25A mRNA and protein, and by inhibition of Cdk2 activity. Both Cdk2 and cdc25A are G1 phase specific genes and Cdk2 is the target of Cdc25A. These studies demonstrate that BR exhibits dual mechanisms of action, first by inhibiting IMPDH, and second by inducing apoptosis, which is associated with repression of components of the cell cycle that are downstream of constitutive c-Myc expression.</description><identifier>ISSN: 1350-9047</identifier><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/sj.cdd.4400546</identifier><identifier>PMID: 10467347</identifier><language>eng</language><publisher>England</publisher><subject>Adenocarcinoma ; Apoptosis - drug effects ; benzamide riboside ; c-Myc protein ; cdc25 Phosphatases - biosynthesis ; cdc25 Phosphatases - genetics ; Cdc25A protein ; Cell Division - drug effects ; Dose-Response Relationship, Drug ; Enzyme Inhibitors - metabolism ; Enzyme Inhibitors - pharmacology ; Female ; Humans ; IMP Dehydrogenase - antagonists & inhibitors ; Nucleosides - metabolism ; Nucleosides - pharmacology ; Ovarian Neoplasms ; Tumor Cells, Cultured</subject><ispartof>Cell death and differentiation, 1999-08, Vol.6 (8), p.736-744</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-d10b2766f87049a1eac08f76f385e37431c521b3eea77870f4cd3f6c913cbf303</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10467347$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Grusch, M</creatorcontrib><creatorcontrib>Rosenberger, G</creatorcontrib><creatorcontrib>Fuhrmann, G</creatorcontrib><creatorcontrib>Braun, K</creatorcontrib><creatorcontrib>Titscher, B</creatorcontrib><creatorcontrib>Szekeres, T</creatorcontrib><creatorcontrib>Fritzer-Skekeres, M</creatorcontrib><creatorcontrib>Oberhuber, G</creatorcontrib><creatorcontrib>Krohn, K</creatorcontrib><creatorcontrib>Hengstschlaeger, M</creatorcontrib><creatorcontrib>Krupitza, G</creatorcontrib><creatorcontrib>Jayaram, H N</creatorcontrib><title>Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><description>One of the mechanisms of action of a new oncolytic agent, benzamide riboside (BR) is by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH) which catalyzes the formation of xanthine 5'-monophosphate from inosine 5'-monophosphate and nicotinamide adenine dinucleotide, thereby restricting the biosynthesis of guanylates. In the present study BR (10 - 20 microM) induced apoptosis in a human ovarian carcinoma N.1 cell line (a monoclonal derivative of its heterogenous parent line HOC-7). This was ascertained by DNA fragmentation, TUNEL assay, [poly(ADP)ribose polymerase]-cleavage and alteration in cell morphology. Apoptosis was accompanied by sustained c-Myc expression, concurrent down-regulation of cdc25A mRNA and protein, and by inhibition of Cdk2 activity. Both Cdk2 and cdc25A are G1 phase specific genes and Cdk2 is the target of Cdc25A. These studies demonstrate that BR exhibits dual mechanisms of action, first by inhibiting IMPDH, and second by inducing apoptosis, which is associated with repression of components of the cell cycle that are downstream of constitutive c-Myc expression.</description><subject>Adenocarcinoma</subject><subject>Apoptosis - drug effects</subject><subject>benzamide riboside</subject><subject>c-Myc protein</subject><subject>cdc25 Phosphatases - biosynthesis</subject><subject>cdc25 Phosphatases - genetics</subject><subject>Cdc25A protein</subject><subject>Cell Division - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Female</subject><subject>Humans</subject><subject>IMP Dehydrogenase - antagonists & inhibitors</subject><subject>Nucleosides - metabolism</subject><subject>Nucleosides - pharmacology</subject><subject>Ovarian Neoplasms</subject><subject>Tumor Cells, Cultured</subject><issn>1350-9047</issn><issn>1476-5403</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkb1PwzAQxS0EoqWwMiJPbAnn2LGTsVR8SRUsMEeOcxapmjjYCQL-ely1AxvL3dPT706ne4RcMkgZ8OImbFLTNKkQALmQR2TOhJJJLoAfR81zSEoQakbOQtgAgFSlPCUzBkIqLtScbG6x_9Fd2yD1be3CTrR9MxkMVA9uGKMVdg4OGEs_UmfpqjFZvqT4NXgMoXV9BOj71Omeuk_t29iN9qbtXafpc8qowe02nJMTq7cBLw59Qd7u715Xj8n65eFptVwnhstsTBoGdaaktIUCUWqG2kBhlbS8yJErwZnJM1ZzRK1UZKwwDbfSlIyb2nLgC3K93zt49zFhGKuuDbsLdI9uCpUCiK_jxb8gUyUHprIIpnvQeBeCR1sNvu20_64YVLsYqrCpYgzVIYY4cHXYPNUdNn_w_d_5L99shDM</recordid><startdate>19990801</startdate><enddate>19990801</enddate><creator>Grusch, M</creator><creator>Rosenberger, G</creator><creator>Fuhrmann, G</creator><creator>Braun, K</creator><creator>Titscher, B</creator><creator>Szekeres, T</creator><creator>Fritzer-Skekeres, M</creator><creator>Oberhuber, G</creator><creator>Krohn, K</creator><creator>Hengstschlaeger, M</creator><creator>Krupitza, G</creator><creator>Jayaram, H N</creator><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>7TO</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>19990801</creationdate><title>Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells</title><author>Grusch, M ; Rosenberger, G ; Fuhrmann, G ; Braun, K ; Titscher, B ; Szekeres, T ; Fritzer-Skekeres, M ; Oberhuber, G ; Krohn, K ; Hengstschlaeger, M ; Krupitza, G ; Jayaram, H N</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-d10b2766f87049a1eac08f76f385e37431c521b3eea77870f4cd3f6c913cbf303</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Adenocarcinoma</topic><topic>Apoptosis - drug effects</topic><topic>benzamide riboside</topic><topic>c-Myc protein</topic><topic>cdc25 Phosphatases - biosynthesis</topic><topic>cdc25 Phosphatases - genetics</topic><topic>Cdc25A protein</topic><topic>Cell Division - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Female</topic><topic>Humans</topic><topic>IMP Dehydrogenase - antagonists & inhibitors</topic><topic>Nucleosides - metabolism</topic><topic>Nucleosides - pharmacology</topic><topic>Ovarian Neoplasms</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grusch, M</creatorcontrib><creatorcontrib>Rosenberger, G</creatorcontrib><creatorcontrib>Fuhrmann, G</creatorcontrib><creatorcontrib>Braun, K</creatorcontrib><creatorcontrib>Titscher, B</creatorcontrib><creatorcontrib>Szekeres, T</creatorcontrib><creatorcontrib>Fritzer-Skekeres, M</creatorcontrib><creatorcontrib>Oberhuber, G</creatorcontrib><creatorcontrib>Krohn, K</creatorcontrib><creatorcontrib>Hengstschlaeger, M</creatorcontrib><creatorcontrib>Krupitza, G</creatorcontrib><creatorcontrib>Jayaram, H N</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cell death and differentiation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grusch, M</au><au>Rosenberger, G</au><au>Fuhrmann, G</au><au>Braun, K</au><au>Titscher, B</au><au>Szekeres, T</au><au>Fritzer-Skekeres, M</au><au>Oberhuber, G</au><au>Krohn, K</au><au>Hengstschlaeger, M</au><au>Krupitza, G</au><au>Jayaram, H N</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells</atitle><jtitle>Cell death and differentiation</jtitle><addtitle>Cell Death Differ</addtitle><date>1999-08-01</date><risdate>1999</risdate><volume>6</volume><issue>8</issue><spage>736</spage><epage>744</epage><pages>736-744</pages><issn>1350-9047</issn><eissn>1476-5403</eissn><abstract>One of the mechanisms of action of a new oncolytic agent, benzamide riboside (BR) is by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH) which catalyzes the formation of xanthine 5'-monophosphate from inosine 5'-monophosphate and nicotinamide adenine dinucleotide, thereby restricting the biosynthesis of guanylates. In the present study BR (10 - 20 microM) induced apoptosis in a human ovarian carcinoma N.1 cell line (a monoclonal derivative of its heterogenous parent line HOC-7). This was ascertained by DNA fragmentation, TUNEL assay, [poly(ADP)ribose polymerase]-cleavage and alteration in cell morphology. Apoptosis was accompanied by sustained c-Myc expression, concurrent down-regulation of cdc25A mRNA and protein, and by inhibition of Cdk2 activity. Both Cdk2 and cdc25A are G1 phase specific genes and Cdk2 is the target of Cdc25A. These studies demonstrate that BR exhibits dual mechanisms of action, first by inhibiting IMPDH, and second by inducing apoptosis, which is associated with repression of components of the cell cycle that are downstream of constitutive c-Myc expression.</abstract><cop>England</cop><pmid>10467347</pmid><doi>10.1038/sj.cdd.4400546</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adenocarcinoma Apoptosis - drug effects benzamide riboside c-Myc protein cdc25 Phosphatases - biosynthesis cdc25 Phosphatases - genetics Cdc25A protein Cell Division - drug effects Dose-Response Relationship, Drug Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacology Female Humans IMP Dehydrogenase - antagonists & inhibitors Nucleosides - metabolism Nucleosides - pharmacology Ovarian Neoplasms Tumor Cells, Cultured |
title | Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells |
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