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An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer
High-grade serous ovarian cancers (HGSCs) are deadly malignancies that relapse despite carboplatin chemotherapy. Here we show that 16 independent primary HGSC samples contain a CA125-negative population enriched for carboplatin-resistant cancer initiating cells. Transcriptome analysis reveals upregu...
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| Published in: | Nature communications 2015-08, Vol.6, p.7956-7956 |
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| container_title | Nature communications |
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| creator | Janzen, D M Tiourin, E Salehi, J A Paik, D Y Lu, J Pellegrini, M Memarzadeh, S |
| description | High-grade serous ovarian cancers (HGSCs) are deadly malignancies that relapse despite carboplatin chemotherapy. Here we show that 16 independent primary HGSC samples contain a CA125-negative population enriched for carboplatin-resistant cancer initiating cells. Transcriptome analysis reveals upregulation of homologous recombination DNA repair and anti-apoptotic signals in this population. While treatment with carboplatin enriches for CA125-negative cells, co-treatment with carboplatin and birinapant eliminates these cells in HGSCs expressing high levels of the inhibitor of apoptosis protein cIAP in the CA125-negative population. Birinapant sensitizes CA125-negative cells to carboplatin by mediating degradation of cIAP causing cleavage of caspase 8 and restoration of apoptosis. This co-therapy significantly improves disease-free survival in vivo compared with either therapy alone in tumour-bearing mice. These findings suggest that therapeutic strategies that target CA125-negative cells may be useful in the treatment of HGSC. |
| doi_str_mv | 10.1038/ncomms8956 |
| format | article |
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Here we show that 16 independent primary HGSC samples contain a CA125-negative population enriched for carboplatin-resistant cancer initiating cells. Transcriptome analysis reveals upregulation of homologous recombination DNA repair and anti-apoptotic signals in this population. While treatment with carboplatin enriches for CA125-negative cells, co-treatment with carboplatin and birinapant eliminates these cells in HGSCs expressing high levels of the inhibitor of apoptosis protein cIAP in the CA125-negative population. Birinapant sensitizes CA125-negative cells to carboplatin by mediating degradation of cIAP causing cleavage of caspase 8 and restoration of apoptosis. This co-therapy significantly improves disease-free survival in vivo compared with either therapy alone in tumour-bearing mice. These findings suggest that therapeutic strategies that target CA125-negative cells may be useful in the treatment of HGSC.</description><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/ncomms8956</identifier><identifier>PMID: 26234182</identifier><language>eng</language><publisher>England: Nature Publishing Group</publisher><subject>Animals ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Apoptosis - genetics ; CA-125 Antigen - metabolism ; Cancer ; Carboplatin ; Carboplatin - pharmacology ; Caspase ; Caspase 8 - drug effects ; Caspase 8 - metabolism ; Caspase-8 ; Chemotherapy ; Dipeptides - pharmacology ; DNA repair ; Drug Resistance, Neoplasm - genetics ; Female ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic - genetics ; Homologous recombination ; Homology ; Humans ; Indoles - pharmacology ; Inhibitor of Apoptosis Proteins - drug effects ; Inhibitor of Apoptosis Proteins - metabolism ; Membrane Proteins - metabolism ; Mice ; Neoplasm Transplantation ; Neoplasms, Cystic, Mucinous, and Serous - drug therapy ; Neoplasms, Cystic, Mucinous, and Serous - genetics ; Ovarian cancer ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - genetics ; Platinum ; Recombinational DNA Repair - genetics ; Restoration ; Tumors ; Up-Regulation</subject><ispartof>Nature communications, 2015-08, Vol.6, p.7956-7956</ispartof><rights>Copyright Nature Publishing Group Aug 2015</rights><rights>Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2015 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1700695332/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1700695332?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26234182$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Janzen, D M</creatorcontrib><creatorcontrib>Tiourin, E</creatorcontrib><creatorcontrib>Salehi, J A</creatorcontrib><creatorcontrib>Paik, D Y</creatorcontrib><creatorcontrib>Lu, J</creatorcontrib><creatorcontrib>Pellegrini, M</creatorcontrib><creatorcontrib>Memarzadeh, S</creatorcontrib><title>An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><description>High-grade serous ovarian cancers (HGSCs) are deadly malignancies that relapse despite carboplatin chemotherapy. Here we show that 16 independent primary HGSC samples contain a CA125-negative population enriched for carboplatin-resistant cancer initiating cells. Transcriptome analysis reveals upregulation of homologous recombination DNA repair and anti-apoptotic signals in this population. While treatment with carboplatin enriches for CA125-negative cells, co-treatment with carboplatin and birinapant eliminates these cells in HGSCs expressing high levels of the inhibitor of apoptosis protein cIAP in the CA125-negative population. Birinapant sensitizes CA125-negative cells to carboplatin by mediating degradation of cIAP causing cleavage of caspase 8 and restoration of apoptosis. This co-therapy significantly improves disease-free survival in vivo compared with either therapy alone in tumour-bearing mice. These findings suggest that therapeutic strategies that target CA125-negative cells may be useful in the treatment of HGSC.</description><subject>Animals</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>CA-125 Antigen - metabolism</subject><subject>Cancer</subject><subject>Carboplatin</subject><subject>Carboplatin - pharmacology</subject><subject>Caspase</subject><subject>Caspase 8 - drug effects</subject><subject>Caspase 8 - metabolism</subject><subject>Caspase-8</subject><subject>Chemotherapy</subject><subject>Dipeptides - pharmacology</subject><subject>DNA repair</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic - genetics</subject><subject>Homologous recombination</subject><subject>Homology</subject><subject>Humans</subject><subject>Indoles - pharmacology</subject><subject>Inhibitor of Apoptosis Proteins - drug effects</subject><subject>Inhibitor of Apoptosis Proteins - metabolism</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Neoplasm Transplantation</subject><subject>Neoplasms, Cystic, Mucinous, and Serous - drug therapy</subject><subject>Neoplasms, Cystic, Mucinous, and Serous - genetics</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Platinum</subject><subject>Recombinational DNA Repair - genetics</subject><subject>Restoration</subject><subject>Tumors</subject><subject>Up-Regulation</subject><issn>2041-1723</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><recordid>eNpdkUtLAzEYRYMgttRu_AEScONmNI95JBuhFF9QcKPrIZPJtCkzyZhHwX9vBquo2WSRcw_3-wLABUY3GFF2a6QdBs94UZ6AOUE5znBF6Awsvd-jdCjHLM_PwIyUhOaYkTkYVwaK0Y7Beu0zZXbCSG22sHVxC-1BuaRUHo69CNrEATqVuJAgBXVKwhAHG12mjQ56QrbQxyb54hSwBtouWYTTwkA5pdw5OO1E79XyeC_A28P96_op27w8Pq9Xm2wkPA8Z4byVHe0qymVOKtpiIqUqC1EghTEvZSV40UjMO4Y4bgkWUlBe5kryphWkpQtw9-UdYzOoVioTnOjr0elBuI_aCl3_fTF6V2_toc4LShgrk-D6KHD2PSof6kF7qfpeGGWjr3GFMOOIsSKhV__QfVqKSeNNFCp5QSlJ1OXvRj9Vvj-DfgJ2ZI4b</recordid><startdate>20150803</startdate><enddate>20150803</enddate><creator>Janzen, D M</creator><creator>Tiourin, E</creator><creator>Salehi, J A</creator><creator>Paik, D Y</creator><creator>Lu, J</creator><creator>Pellegrini, M</creator><creator>Memarzadeh, S</creator><general>Nature Publishing Group</general><general>Nature Pub. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Janzen, D M</au><au>Tiourin, E</au><au>Salehi, J A</au><au>Paik, D Y</au><au>Lu, J</au><au>Pellegrini, M</au><au>Memarzadeh, S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer</atitle><jtitle>Nature communications</jtitle><addtitle>Nat Commun</addtitle><date>2015-08-03</date><risdate>2015</risdate><volume>6</volume><spage>7956</spage><epage>7956</epage><pages>7956-7956</pages><eissn>2041-1723</eissn><abstract>High-grade serous ovarian cancers (HGSCs) are deadly malignancies that relapse despite carboplatin chemotherapy. Here we show that 16 independent primary HGSC samples contain a CA125-negative population enriched for carboplatin-resistant cancer initiating cells. Transcriptome analysis reveals upregulation of homologous recombination DNA repair and anti-apoptotic signals in this population. While treatment with carboplatin enriches for CA125-negative cells, co-treatment with carboplatin and birinapant eliminates these cells in HGSCs expressing high levels of the inhibitor of apoptosis protein cIAP in the CA125-negative population. Birinapant sensitizes CA125-negative cells to carboplatin by mediating degradation of cIAP causing cleavage of caspase 8 and restoration of apoptosis. This co-therapy significantly improves disease-free survival in vivo compared with either therapy alone in tumour-bearing mice. These findings suggest that therapeutic strategies that target CA125-negative cells may be useful in the treatment of HGSC.</abstract><cop>England</cop><pub>Nature Publishing Group</pub><pmid>26234182</pmid><doi>10.1038/ncomms8956</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology Apoptosis Apoptosis - drug effects Apoptosis - genetics CA-125 Antigen - metabolism Cancer Carboplatin Carboplatin - pharmacology Caspase Caspase 8 - drug effects Caspase 8 - metabolism Caspase-8 Chemotherapy Dipeptides - pharmacology DNA repair Drug Resistance, Neoplasm - genetics Female Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic - genetics Homologous recombination Homology Humans Indoles - pharmacology Inhibitor of Apoptosis Proteins - drug effects Inhibitor of Apoptosis Proteins - metabolism Membrane Proteins - metabolism Mice Neoplasm Transplantation Neoplasms, Cystic, Mucinous, and Serous - drug therapy Neoplasms, Cystic, Mucinous, and Serous - genetics Ovarian cancer Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Platinum Recombinational DNA Repair - genetics Restoration Tumors Up-Regulation |
| title | An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer |
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