Aberrant DNA damage response pathways may predict the outcome of platinum chemotherapy in ovarian cancer
Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothe...
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| creator | Stefanou, Dimitra T Bamias, Aristotelis Episkopou, Hara Kyrtopoulos, Soterios A Likka, Maria Kalampokas, Theodore Photiou, Stylianos Gavalas, Nikos Sfikakis, Petros P Dimopoulos, Meletios A Souliotis, Vassilis L |
| description | Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothesis that DNA damage response (DDR) pathways are involved in resistance of OC patients to platinum chemotherapy. Selected DDR signals were evaluated in two human ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/C30) to platinum treatment as well as in peripheral blood mononuclear cells (PBMCs) from OC patients, sensitive (n = 7) or resistant (n = 4) to subsequent chemotherapy. PBMCs from healthy volunteers (n = 9) were studied in parallel. DNA damage was evaluated by immunofluorescence γH2AX staining and comet assay. Higher levels of intrinsic DNA damage were found in A2780 than in A2780/C30 cells. Moreover, the intrinsic DNA damage levels were significantly higher in OC patients relative to healthy volunteers, as well as in platinum-sensitive patients relative to platinum-resistant ones (all P |
| doi_str_mv | 10.1371/journal.pone.0117654 |
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Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothesis that DNA damage response (DDR) pathways are involved in resistance of OC patients to platinum chemotherapy. Selected DDR signals were evaluated in two human ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/C30) to platinum treatment as well as in peripheral blood mononuclear cells (PBMCs) from OC patients, sensitive (n = 7) or resistant (n = 4) to subsequent chemotherapy. PBMCs from healthy volunteers (n = 9) were studied in parallel. DNA damage was evaluated by immunofluorescence γH2AX staining and comet assay. Higher levels of intrinsic DNA damage were found in A2780 than in A2780/C30 cells. Moreover, the intrinsic DNA damage levels were significantly higher in OC patients relative to healthy volunteers, as well as in platinum-sensitive patients relative to platinum-resistant ones (all P<0.05). Following carboplatin treatment, A2780 cells showed lower DNA repair efficiency than A2780/C30 cells. Also, following carboplatin treatment of PBMCs ex vivo, the DNA repair efficiency was significantly higher in healthy volunteers than in platinum-resistant patients and lowest in platinum-sensitive ones (t1/2 for loss of γH2AX foci: 2.7±0.5h, 8.8±1.9h and 15.4±3.2h, respectively; using comet assay, t1/2 of platinum-induced damage repair: 4.8±1.4h, 12.9±1.9h and 21.4±2.6h, respectively; all P<0.03). Additionally, the carboplatin-induced apoptosis rate was higher in A2780 than in A2780/C30 cells. In PBMCs, apoptosis rates were inversely correlated with DNA repair efficiencies of these cells, being significantly higher in platinum-sensitive than in platinum-resistant patients and lowest in healthy volunteers (all P<0.05). We conclude that perturbations of DNA repair pathways as measured in PBMCs from OC patients correlate with the drug sensitivity of these cells and reflect the individualized response to platinum-based chemotherapy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0117654</identifier><identifier>PMID: 25659114</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Aged ; Antineoplastic Agents - administration & dosage ; Apoptosis ; Apoptosis - drug effects ; Bioassays ; Biology ; Biotechnology ; Blood ; Breast cancer ; Cancer genetics ; Cancer therapies ; Carboplatin ; Carboplatin - administration & dosage ; Cell Line, Tumor ; Chemoresistance ; Chemotherapy ; Clinical medicine ; Combinatorial analysis ; Comet assay ; Cytotoxicity ; Damage assessment ; Damage detection ; Deoxyribonucleic acid ; Disease-Free Survival ; DNA ; DNA Damage ; DNA methylation ; DNA repair ; DNA Repair - drug effects ; Drug Resistance, Neoplasm - drug effects ; Epigenetics ; Female ; Follow-Up Studies ; Gene expression ; Genetic research ; Genomes ; Gynecology ; Humans ; Immunofluorescence ; Leukocytes (mononuclear) ; Lung cancer ; Malignancy ; Medical prognosis ; Medical schools ; Middle Aged ; Obstetrics ; Ovarian cancer ; Ovarian carcinoma ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - mortality ; Patients ; Peripheral blood mononuclear cells ; Pharmaceutical sciences ; Platinum ; Platinum - administration & dosage ; Prognosis ; Repair ; Signal transduction ; Surgery ; Survival Rate ; Toxicity ; Tumor cell lines ; Tumors</subject><ispartof>PloS one, 2015-02, Vol.10 (2), p.e0117654</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Stefanou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Stefanou et al 2015 Stefanou et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-5070831ef6529691995700b1edc7f18c561db862ea40dce9b6aaea4cc0b9fd0f3</citedby><cites>FETCH-LOGICAL-c692t-5070831ef6529691995700b1edc7f18c561db862ea40dce9b6aaea4cc0b9fd0f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320060/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320060/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,2098,2917,23853,27911,27912,53778,53780,79355,79356</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25659114$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Samimi, Goli</contributor><creatorcontrib>Stefanou, Dimitra T</creatorcontrib><creatorcontrib>Bamias, Aristotelis</creatorcontrib><creatorcontrib>Episkopou, Hara</creatorcontrib><creatorcontrib>Kyrtopoulos, Soterios A</creatorcontrib><creatorcontrib>Likka, Maria</creatorcontrib><creatorcontrib>Kalampokas, Theodore</creatorcontrib><creatorcontrib>Photiou, Stylianos</creatorcontrib><creatorcontrib>Gavalas, Nikos</creatorcontrib><creatorcontrib>Sfikakis, Petros P</creatorcontrib><creatorcontrib>Dimopoulos, Meletios A</creatorcontrib><creatorcontrib>Souliotis, Vassilis L</creatorcontrib><title>Aberrant DNA damage response pathways may predict the outcome of platinum chemotherapy in ovarian cancer</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothesis that DNA damage response (DDR) pathways are involved in resistance of OC patients to platinum chemotherapy. Selected DDR signals were evaluated in two human ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/C30) to platinum treatment as well as in peripheral blood mononuclear cells (PBMCs) from OC patients, sensitive (n = 7) or resistant (n = 4) to subsequent chemotherapy. PBMCs from healthy volunteers (n = 9) were studied in parallel. DNA damage was evaluated by immunofluorescence γH2AX staining and comet assay. Higher levels of intrinsic DNA damage were found in A2780 than in A2780/C30 cells. Moreover, the intrinsic DNA damage levels were significantly higher in OC patients relative to healthy volunteers, as well as in platinum-sensitive patients relative to platinum-resistant ones (all P<0.05). Following carboplatin treatment, A2780 cells showed lower DNA repair efficiency than A2780/C30 cells. Also, following carboplatin treatment of PBMCs ex vivo, the DNA repair efficiency was significantly higher in healthy volunteers than in platinum-resistant patients and lowest in platinum-sensitive ones (t1/2 for loss of γH2AX foci: 2.7±0.5h, 8.8±1.9h and 15.4±3.2h, respectively; using comet assay, t1/2 of platinum-induced damage repair: 4.8±1.4h, 12.9±1.9h and 21.4±2.6h, respectively; all P<0.03). Additionally, the carboplatin-induced apoptosis rate was higher in A2780 than in A2780/C30 cells. In PBMCs, apoptosis rates were inversely correlated with DNA repair efficiencies of these cells, being significantly higher in platinum-sensitive than in platinum-resistant patients and lowest in healthy volunteers (all P<0.05). We conclude that perturbations of DNA repair pathways as measured in PBMCs from OC patients correlate with the drug sensitivity of these cells and reflect the individualized response to platinum-based chemotherapy.</description><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Bioassays</subject><subject>Biology</subject><subject>Biotechnology</subject><subject>Blood</subject><subject>Breast cancer</subject><subject>Cancer genetics</subject><subject>Cancer therapies</subject><subject>Carboplatin</subject><subject>Carboplatin - administration & dosage</subject><subject>Cell Line, Tumor</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>Clinical medicine</subject><subject>Combinatorial analysis</subject><subject>Comet assay</subject><subject>Cytotoxicity</subject><subject>Damage assessment</subject><subject>Damage detection</subject><subject>Deoxyribonucleic acid</subject><subject>Disease-Free Survival</subject><subject>DNA</subject><subject>DNA Damage</subject><subject>DNA methylation</subject><subject>DNA repair</subject><subject>DNA Repair - drug effects</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Epigenetics</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Gene expression</subject><subject>Genetic research</subject><subject>Genomes</subject><subject>Gynecology</subject><subject>Humans</subject><subject>Immunofluorescence</subject><subject>Leukocytes (mononuclear)</subject><subject>Lung cancer</subject><subject>Malignancy</subject><subject>Medical prognosis</subject><subject>Medical schools</subject><subject>Middle Aged</subject><subject>Obstetrics</subject><subject>Ovarian cancer</subject><subject>Ovarian carcinoma</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Ovarian Neoplasms - mortality</subject><subject>Patients</subject><subject>Peripheral blood mononuclear cells</subject><subject>Pharmaceutical sciences</subject><subject>Platinum</subject><subject>Platinum - administration & dosage</subject><subject>Prognosis</subject><subject>Repair</subject><subject>Signal transduction</subject><subject>Surgery</subject><subject>Survival Rate</subject><subject>Toxicity</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkm2L1DAQx4so3nn6DUQDguCLXZM-pM0bYTmfFg4PfHobpulkm6NtapKe7rc35_aOLShIXkyY-c1_huGfJE8ZXbOsZK-v7OQG6NajHXBNGSt5kd9LTpnI0hVPaXb_6H-SPPL-itIiqzh_mJykBS8EY_lp0m5qdA6GQN5-2pAGetghceijqkcyQmh_wt6THvZkdNgYFUhokdgpKNvHqMnYQTDD1BPVYm9j0cG4J2Yg9hqcgYEoGBS6x8kDDZ3HJ3M8S769f_f1_OPq4vLD9nxzsVJcpGFV0JJWGUPNi1RwwYQoSkprho0qNatUwVlTVzxFyGmjUNQcIP6VorXQDdXZWfL8oDt21sv5SF6yqMcEr2gZie2BaCxcydGZHtxeWjDyT8K6nQQXjOpQsjiEl4w2tMlzjQKYRl3UrEaqWJVC1HozT5vqPu6IQ3DQLUSXlcG0cmevZZ6llHIaBV7MAs7-mNCHf6w8UzuIW5lB2yimeuOV3OSpqFiZ8TxS679Q8TXYGxVtok3MLxpeLRoiE_BX2MHkvdx--fz_7OX3JfvyiG0RutB6203BRFctwfwAKme9d6jvLseovHH57TXkjcvl7PLY9uz46ndNt7bOfgNW0_jt</recordid><startdate>20150206</startdate><enddate>20150206</enddate><creator>Stefanou, Dimitra T</creator><creator>Bamias, Aristotelis</creator><creator>Episkopou, Hara</creator><creator>Kyrtopoulos, Soterios A</creator><creator>Likka, Maria</creator><creator>Kalampokas, Theodore</creator><creator>Photiou, Stylianos</creator><creator>Gavalas, Nikos</creator><creator>Sfikakis, Petros P</creator><creator>Dimopoulos, Meletios A</creator><creator>Souliotis, Vassilis L</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150206</creationdate><title>Aberrant DNA damage response pathways may predict the outcome of platinum chemotherapy in ovarian cancer</title><author>Stefanou, Dimitra T ; Bamias, Aristotelis ; Episkopou, Hara ; Kyrtopoulos, Soterios A ; Likka, Maria ; Kalampokas, Theodore ; Photiou, Stylianos ; Gavalas, Nikos ; Sfikakis, Petros P ; Dimopoulos, Meletios A ; Souliotis, Vassilis L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-5070831ef6529691995700b1edc7f18c561db862ea40dce9b6aaea4cc0b9fd0f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antineoplastic Agents - 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drug therapy</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Ovarian Neoplasms - metabolism</topic><topic>Ovarian Neoplasms - mortality</topic><topic>Patients</topic><topic>Peripheral blood mononuclear cells</topic><topic>Pharmaceutical sciences</topic><topic>Platinum</topic><topic>Platinum - administration & dosage</topic><topic>Prognosis</topic><topic>Repair</topic><topic>Signal transduction</topic><topic>Surgery</topic><topic>Survival Rate</topic><topic>Toxicity</topic><topic>Tumor cell lines</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Stefanou, Dimitra T</creatorcontrib><creatorcontrib>Bamias, Aristotelis</creatorcontrib><creatorcontrib>Episkopou, Hara</creatorcontrib><creatorcontrib>Kyrtopoulos, Soterios A</creatorcontrib><creatorcontrib>Likka, Maria</creatorcontrib><creatorcontrib>Kalampokas, Theodore</creatorcontrib><creatorcontrib>Photiou, Stylianos</creatorcontrib><creatorcontrib>Gavalas, Nikos</creatorcontrib><creatorcontrib>Sfikakis, Petros P</creatorcontrib><creatorcontrib>Dimopoulos, Meletios A</creatorcontrib><creatorcontrib>Souliotis, Vassilis L</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Stefanou, Dimitra T</au><au>Bamias, Aristotelis</au><au>Episkopou, Hara</au><au>Kyrtopoulos, Soterios A</au><au>Likka, Maria</au><au>Kalampokas, Theodore</au><au>Photiou, Stylianos</au><au>Gavalas, Nikos</au><au>Sfikakis, Petros P</au><au>Dimopoulos, Meletios A</au><au>Souliotis, Vassilis L</au><au>Samimi, Goli</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aberrant DNA damage response pathways may predict the outcome of platinum chemotherapy in ovarian cancer</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-02-06</date><risdate>2015</risdate><volume>10</volume><issue>2</issue><spage>e0117654</spage><pages>e0117654-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothesis that DNA damage response (DDR) pathways are involved in resistance of OC patients to platinum chemotherapy. Selected DDR signals were evaluated in two human ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/C30) to platinum treatment as well as in peripheral blood mononuclear cells (PBMCs) from OC patients, sensitive (n = 7) or resistant (n = 4) to subsequent chemotherapy. PBMCs from healthy volunteers (n = 9) were studied in parallel. DNA damage was evaluated by immunofluorescence γH2AX staining and comet assay. Higher levels of intrinsic DNA damage were found in A2780 than in A2780/C30 cells. Moreover, the intrinsic DNA damage levels were significantly higher in OC patients relative to healthy volunteers, as well as in platinum-sensitive patients relative to platinum-resistant ones (all P<0.05). Following carboplatin treatment, A2780 cells showed lower DNA repair efficiency than A2780/C30 cells. Also, following carboplatin treatment of PBMCs ex vivo, the DNA repair efficiency was significantly higher in healthy volunteers than in platinum-resistant patients and lowest in platinum-sensitive ones (t1/2 for loss of γH2AX foci: 2.7±0.5h, 8.8±1.9h and 15.4±3.2h, respectively; using comet assay, t1/2 of platinum-induced damage repair: 4.8±1.4h, 12.9±1.9h and 21.4±2.6h, respectively; all P<0.03). Additionally, the carboplatin-induced apoptosis rate was higher in A2780 than in A2780/C30 cells. In PBMCs, apoptosis rates were inversely correlated with DNA repair efficiencies of these cells, being significantly higher in platinum-sensitive than in platinum-resistant patients and lowest in healthy volunteers (all P<0.05). We conclude that perturbations of DNA repair pathways as measured in PBMCs from OC patients correlate with the drug sensitivity of these cells and reflect the individualized response to platinum-based chemotherapy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25659114</pmid><doi>10.1371/journal.pone.0117654</doi><tpages>e0117654</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-02, Vol.10 (2), p.e0117654 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1652196807 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adult Aged Antineoplastic Agents - administration & dosage Apoptosis Apoptosis - drug effects Bioassays Biology Biotechnology Blood Breast cancer Cancer genetics Cancer therapies Carboplatin Carboplatin - administration & dosage Cell Line, Tumor Chemoresistance Chemotherapy Clinical medicine Combinatorial analysis Comet assay Cytotoxicity Damage assessment Damage detection Deoxyribonucleic acid Disease-Free Survival DNA DNA Damage DNA methylation DNA repair DNA Repair - drug effects Drug Resistance, Neoplasm - drug effects Epigenetics Female Follow-Up Studies Gene expression Genetic research Genomes Gynecology Humans Immunofluorescence Leukocytes (mononuclear) Lung cancer Malignancy Medical prognosis Medical schools Middle Aged Obstetrics Ovarian cancer Ovarian carcinoma Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - metabolism Ovarian Neoplasms - mortality Patients Peripheral blood mononuclear cells Pharmaceutical sciences Platinum Platinum - administration & dosage Prognosis Repair Signal transduction Surgery Survival Rate Toxicity Tumor cell lines Tumors |
| title | Aberrant DNA damage response pathways may predict the outcome of platinum chemotherapy in ovarian cancer |
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