Poly(ADP-ribose) polymerase inhibitor CEP-8983 synergizes with bendamustine in chronic lymphocytic leukemia cells in vitro
Abstract DNA repair aberrations and associated chromosomal instability is a feature of chronic lymphocytic leukemia (CLL). To evaluate if DNA repair insufficiencies are related to methylation changes, we examined the methylation of nine promoter regions of DNA repair proteins by bisulfide sequencing...
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| Veröffentlicht in: | Leukemia research 2014-03, Vol.38 (3), p.411-417 |
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| creator | Dilley, Robert L Poh, Weijie Gladstone, Douglas E Herman, James G Showel, Margaret M Karp, Judith E McDevitt, Michael A Pratz, Keith W |
| description | Abstract DNA repair aberrations and associated chromosomal instability is a feature of chronic lymphocytic leukemia (CLL). To evaluate if DNA repair insufficiencies are related to methylation changes, we examined the methylation of nine promoter regions of DNA repair proteins by bisulfide sequencing in 26 CLL primary samples and performed quantitative PCR on a subset of samples to examine BRCA1 expression. We also investigated if changes in cytogenetic or expression level of DNA repair proteins led to changes in sensitivity to a novel PARP inhibitor, CEP-8983, alone and in combination with bendamustine. No changes in promoter methylation were identified in BRCA1, BRCA2, FANC-C, FANC-F, FANC-L, ATM, MGMT, hMLH1 and H2AX except for two cases of minor BRCA1 hypermethylation. CLL samples appeared to have reduced BRCA1 mRNA expression uniformly in comparison to non-malignant lymphocytes irrespective of promoter hypermethylation. CEP-8983 displayed single agent cytotoxicity and the combination with bendamustine demonstrated synergistic cytotoxicity in the majority of CLL samples. These results were consistent across cytogenetic subgroups, including 17p deleted and previously treated patients. Our results provide rationale for further exploration of the combination of a PARP inhibitor and DNA damaging agents as a novel therapeutic strategy in CLL. |
| doi_str_mv | 10.1016/j.leukres.2013.12.019 |
| format | Article |
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To evaluate if DNA repair insufficiencies are related to methylation changes, we examined the methylation of nine promoter regions of DNA repair proteins by bisulfide sequencing in 26 CLL primary samples and performed quantitative PCR on a subset of samples to examine BRCA1 expression. We also investigated if changes in cytogenetic or expression level of DNA repair proteins led to changes in sensitivity to a novel PARP inhibitor, CEP-8983, alone and in combination with bendamustine. No changes in promoter methylation were identified in BRCA1, BRCA2, FANC-C, FANC-F, FANC-L, ATM, MGMT, hMLH1 and H2AX except for two cases of minor BRCA1 hypermethylation. CLL samples appeared to have reduced BRCA1 mRNA expression uniformly in comparison to non-malignant lymphocytes irrespective of promoter hypermethylation. CEP-8983 displayed single agent cytotoxicity and the combination with bendamustine demonstrated synergistic cytotoxicity in the majority of CLL samples. These results were consistent across cytogenetic subgroups, including 17p deleted and previously treated patients. Our results provide rationale for further exploration of the combination of a PARP inhibitor and DNA damaging agents as a novel therapeutic strategy in CLL.</description><identifier>ISSN: 0145-2126</identifier><identifier>EISSN: 1873-5835</identifier><identifier>DOI: 10.1016/j.leukres.2013.12.019</identifier><identifier>PMID: 24439051</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Antineoplastic Agents, Alkylating - pharmacology ; B-Lymphocytes - drug effects ; B-Lymphocytes - metabolism ; B-Lymphocytes - pathology ; Bendamustine ; Bendamustine Hydrochloride ; BRCA1 Protein - genetics ; BRCA1 Protein - metabolism ; Carbazoles - pharmacology ; CEP-8983 ; Chronic lymphocytic leukemia (CLL) ; DNA Damage ; DNA Methylation - drug effects ; DNA Repair - drug effects ; DNA Repair Enzymes - genetics ; DNA Repair Enzymes - metabolism ; DNA, Neoplasm - antagonists & inhibitors ; DNA, Neoplasm - genetics ; DNA, Neoplasm - metabolism ; Drug Synergism ; Enzyme Inhibitors - pharmacology ; Gene Expression Regulation, Leukemic - drug effects ; Hematology, Oncology and Palliative Medicine ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell - genetics ; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell - pathology ; Nitrogen Mustard Compounds - pharmacology ; Phthalimides - pharmacology ; Poly(ADP-ribose) polymerase (PARP) ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases - genetics ; Poly(ADP-ribose) Polymerases - metabolism ; Promoter Regions, Genetic - drug effects ; Sequence Analysis, DNA ; Signal Transduction</subject><ispartof>Leukemia research, 2014-03, Vol.38 (3), p.411-417</ispartof><rights>Elsevier Ltd</rights><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. All rights reserved.</rights><rights>2013 Elsevier Ltd. All rights reserved. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c555t-743ce74936093e6954543de0a00ecb7f654d2f3bc816687187d1f8b9721e245a3</citedby><cites>FETCH-LOGICAL-c555t-743ce74936093e6954543de0a00ecb7f654d2f3bc816687187d1f8b9721e245a3</cites><orcidid>0000-0001-7358-9088 ; 0000-0002-2112-8842</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0145212613004517$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24439051$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dilley, Robert L</creatorcontrib><creatorcontrib>Poh, Weijie</creatorcontrib><creatorcontrib>Gladstone, Douglas E</creatorcontrib><creatorcontrib>Herman, James G</creatorcontrib><creatorcontrib>Showel, Margaret M</creatorcontrib><creatorcontrib>Karp, Judith E</creatorcontrib><creatorcontrib>McDevitt, Michael A</creatorcontrib><creatorcontrib>Pratz, Keith W</creatorcontrib><title>Poly(ADP-ribose) polymerase inhibitor CEP-8983 synergizes with bendamustine in chronic lymphocytic leukemia cells in vitro</title><title>Leukemia research</title><addtitle>Leuk Res</addtitle><description>Abstract DNA repair aberrations and associated chromosomal instability is a feature of chronic lymphocytic leukemia (CLL). To evaluate if DNA repair insufficiencies are related to methylation changes, we examined the methylation of nine promoter regions of DNA repair proteins by bisulfide sequencing in 26 CLL primary samples and performed quantitative PCR on a subset of samples to examine BRCA1 expression. We also investigated if changes in cytogenetic or expression level of DNA repair proteins led to changes in sensitivity to a novel PARP inhibitor, CEP-8983, alone and in combination with bendamustine. No changes in promoter methylation were identified in BRCA1, BRCA2, FANC-C, FANC-F, FANC-L, ATM, MGMT, hMLH1 and H2AX except for two cases of minor BRCA1 hypermethylation. CLL samples appeared to have reduced BRCA1 mRNA expression uniformly in comparison to non-malignant lymphocytes irrespective of promoter hypermethylation. CEP-8983 displayed single agent cytotoxicity and the combination with bendamustine demonstrated synergistic cytotoxicity in the majority of CLL samples. These results were consistent across cytogenetic subgroups, including 17p deleted and previously treated patients. Our results provide rationale for further exploration of the combination of a PARP inhibitor and DNA damaging agents as a novel therapeutic strategy in CLL.</description><subject>Antineoplastic Agents, Alkylating - pharmacology</subject><subject>B-Lymphocytes - drug effects</subject><subject>B-Lymphocytes - metabolism</subject><subject>B-Lymphocytes - pathology</subject><subject>Bendamustine</subject><subject>Bendamustine Hydrochloride</subject><subject>BRCA1 Protein - genetics</subject><subject>BRCA1 Protein - metabolism</subject><subject>Carbazoles - pharmacology</subject><subject>CEP-8983</subject><subject>Chronic lymphocytic leukemia (CLL)</subject><subject>DNA Damage</subject><subject>DNA Methylation - drug effects</subject><subject>DNA Repair - drug effects</subject><subject>DNA Repair Enzymes - genetics</subject><subject>DNA Repair Enzymes - metabolism</subject><subject>DNA, Neoplasm - antagonists & inhibitors</subject><subject>DNA, Neoplasm - genetics</subject><subject>DNA, Neoplasm - metabolism</subject><subject>Drug Synergism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Gene Expression Regulation, Leukemic - drug effects</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Humans</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - genetics</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</subject><subject>Nitrogen Mustard Compounds - pharmacology</subject><subject>Phthalimides - pharmacology</subject><subject>Poly(ADP-ribose) polymerase (PARP)</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors</subject><subject>Poly(ADP-ribose) Polymerases - genetics</subject><subject>Poly(ADP-ribose) Polymerases - metabolism</subject><subject>Promoter Regions, Genetic - drug effects</subject><subject>Sequence Analysis, DNA</subject><subject>Signal Transduction</subject><issn>0145-2126</issn><issn>1873-5835</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkk1v1DAQhi0EotuFnwDKsT0keGI7H5eiaikfUiVWAs6W40wab5N4sZNF6a-vo10q4MLJluedd2b8DCFvgCZAIXu3Szqc7h36JKXAEkgTCuUzsoIiZ7EomHhOVhS4iFNIszNy7v2OUipKKF-Ss5RzVlIBK_Kwtd18cf1hGztTWY-X0T489OiUx8gMranMaF20udnGRVmwyM8DujvzgD76ZcY2qnCoVT_50QyLPtKts4PRUfDYt1bP43IPjWJvVKSx6_yiOpjR2VfkRaM6j69P55r8-HjzffM5vv366cvm-jbWQogxzjnTmPOSZbRkmJWCC85qpIpS1FXeZILXacMqXUCWFXmYv4amqMo8BUy5UGxNro6--6nqsdY4jE51cu9Mr9wsrTLy78hgWnlnD5IDT0UovyYXJwNnf07oR9kbv8yiBrSTlyAgy4Xg5SIVR6l21nuHzVMZoHLhJnfyxE0u3CSkMnALeW__7PEp6zeoIHh_FGD4qYNBJ702OGisjUM9ytqa_5a4-sdBdyagUt09zuh3dnJDwCBB-pAgvy3Ls-wOMEq5gJw9AkWPwtU</recordid><startdate>20140301</startdate><enddate>20140301</enddate><creator>Dilley, Robert L</creator><creator>Poh, Weijie</creator><creator>Gladstone, Douglas E</creator><creator>Herman, James G</creator><creator>Showel, Margaret M</creator><creator>Karp, Judith E</creator><creator>McDevitt, Michael A</creator><creator>Pratz, Keith W</creator><general>Elsevier Ltd</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>7T5</scope><scope>H94</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7358-9088</orcidid><orcidid>https://orcid.org/0000-0002-2112-8842</orcidid></search><sort><creationdate>20140301</creationdate><title>Poly(ADP-ribose) polymerase inhibitor CEP-8983 synergizes with bendamustine in chronic lymphocytic leukemia cells in vitro</title><author>Dilley, Robert L ; Poh, Weijie ; Gladstone, Douglas E ; Herman, James G ; Showel, Margaret M ; Karp, Judith E ; McDevitt, Michael A ; Pratz, Keith W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c555t-743ce74936093e6954543de0a00ecb7f654d2f3bc816687187d1f8b9721e245a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Antineoplastic Agents, Alkylating - pharmacology</topic><topic>B-Lymphocytes - drug effects</topic><topic>B-Lymphocytes - metabolism</topic><topic>B-Lymphocytes - pathology</topic><topic>Bendamustine</topic><topic>Bendamustine Hydrochloride</topic><topic>BRCA1 Protein - genetics</topic><topic>BRCA1 Protein - metabolism</topic><topic>Carbazoles - pharmacology</topic><topic>CEP-8983</topic><topic>Chronic lymphocytic leukemia (CLL)</topic><topic>DNA Damage</topic><topic>DNA Methylation - drug effects</topic><topic>DNA Repair - drug effects</topic><topic>DNA Repair Enzymes - genetics</topic><topic>DNA Repair Enzymes - metabolism</topic><topic>DNA, Neoplasm - antagonists & inhibitors</topic><topic>DNA, Neoplasm - genetics</topic><topic>DNA, Neoplasm - metabolism</topic><topic>Drug Synergism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Gene Expression Regulation, Leukemic - drug effects</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Humans</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - genetics</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</topic><topic>Nitrogen Mustard Compounds - pharmacology</topic><topic>Phthalimides - pharmacology</topic><topic>Poly(ADP-ribose) polymerase (PARP)</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors</topic><topic>Poly(ADP-ribose) Polymerases - genetics</topic><topic>Poly(ADP-ribose) Polymerases - metabolism</topic><topic>Promoter Regions, Genetic - drug effects</topic><topic>Sequence Analysis, DNA</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dilley, Robert L</creatorcontrib><creatorcontrib>Poh, Weijie</creatorcontrib><creatorcontrib>Gladstone, Douglas E</creatorcontrib><creatorcontrib>Herman, James G</creatorcontrib><creatorcontrib>Showel, Margaret M</creatorcontrib><creatorcontrib>Karp, Judith E</creatorcontrib><creatorcontrib>McDevitt, Michael A</creatorcontrib><creatorcontrib>Pratz, Keith W</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Leukemia research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dilley, Robert L</au><au>Poh, Weijie</au><au>Gladstone, Douglas E</au><au>Herman, James G</au><au>Showel, Margaret M</au><au>Karp, Judith E</au><au>McDevitt, Michael A</au><au>Pratz, Keith W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Poly(ADP-ribose) polymerase inhibitor CEP-8983 synergizes with bendamustine in chronic lymphocytic leukemia cells in vitro</atitle><jtitle>Leukemia research</jtitle><addtitle>Leuk Res</addtitle><date>2014-03-01</date><risdate>2014</risdate><volume>38</volume><issue>3</issue><spage>411</spage><epage>417</epage><pages>411-417</pages><issn>0145-2126</issn><eissn>1873-5835</eissn><abstract>Abstract DNA repair aberrations and associated chromosomal instability is a feature of chronic lymphocytic leukemia (CLL). To evaluate if DNA repair insufficiencies are related to methylation changes, we examined the methylation of nine promoter regions of DNA repair proteins by bisulfide sequencing in 26 CLL primary samples and performed quantitative PCR on a subset of samples to examine BRCA1 expression. We also investigated if changes in cytogenetic or expression level of DNA repair proteins led to changes in sensitivity to a novel PARP inhibitor, CEP-8983, alone and in combination with bendamustine. No changes in promoter methylation were identified in BRCA1, BRCA2, FANC-C, FANC-F, FANC-L, ATM, MGMT, hMLH1 and H2AX except for two cases of minor BRCA1 hypermethylation. CLL samples appeared to have reduced BRCA1 mRNA expression uniformly in comparison to non-malignant lymphocytes irrespective of promoter hypermethylation. CEP-8983 displayed single agent cytotoxicity and the combination with bendamustine demonstrated synergistic cytotoxicity in the majority of CLL samples. These results were consistent across cytogenetic subgroups, including 17p deleted and previously treated patients. Our results provide rationale for further exploration of the combination of a PARP inhibitor and DNA damaging agents as a novel therapeutic strategy in CLL.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>24439051</pmid><doi>10.1016/j.leukres.2013.12.019</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-7358-9088</orcidid><orcidid>https://orcid.org/0000-0002-2112-8842</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Leukemia research, 2014-03, Vol.38 (3), p.411-417 |
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| subjects | Antineoplastic Agents, Alkylating - pharmacology B-Lymphocytes - drug effects B-Lymphocytes - metabolism B-Lymphocytes - pathology Bendamustine Bendamustine Hydrochloride BRCA1 Protein - genetics BRCA1 Protein - metabolism Carbazoles - pharmacology CEP-8983 Chronic lymphocytic leukemia (CLL) DNA Damage DNA Methylation - drug effects DNA Repair - drug effects DNA Repair Enzymes - genetics DNA Repair Enzymes - metabolism DNA, Neoplasm - antagonists & inhibitors DNA, Neoplasm - genetics DNA, Neoplasm - metabolism Drug Synergism Enzyme Inhibitors - pharmacology Gene Expression Regulation, Leukemic - drug effects Hematology, Oncology and Palliative Medicine Humans Leukemia, Lymphocytic, Chronic, B-Cell - genetics Leukemia, Lymphocytic, Chronic, B-Cell - metabolism Leukemia, Lymphocytic, Chronic, B-Cell - pathology Nitrogen Mustard Compounds - pharmacology Phthalimides - pharmacology Poly(ADP-ribose) polymerase (PARP) Poly(ADP-ribose) Polymerase Inhibitors Poly(ADP-ribose) Polymerases - genetics Poly(ADP-ribose) Polymerases - metabolism Promoter Regions, Genetic - drug effects Sequence Analysis, DNA Signal Transduction |
| title | Poly(ADP-ribose) polymerase inhibitor CEP-8983 synergizes with bendamustine in chronic lymphocytic leukemia cells in vitro |
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