{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T02:50:04Z","timestamp":1762051804345,"version":"build-2065373602"},"reference-count":77,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,5,26]],"date-time":"2022-05-26T00:00:00Z","timestamp":1653523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sharpe-Strumia Research Foundation","award":["SSRF2018-12"],"award-info":[{"award-number":["SSRF2018-12"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Ovarian cancer accounts for 3% of the total cancers in women, yet it is the fifth leading cause of cancer deaths among women. The BRCA1\/2 germline and somatic mutations confer a deficiency of the homologous recombination (HR) repair pathway. Inhibitors of poly (ADP-ribose) polymerase (PARP), another important component of DNA damage repair, are somewhat effective in BRCA1\/2 mutant tumors. However, ovarian cancers often reacquire functional BRCA and develop resistance to PARP inhibitors. Polyamines have been reported to facilitate the DNA damage repair functions of PARP. Given the elevated levels of polyamines in tumors, we hypothesized that treatment with the polyamine synthesis inhibitor, \u03b1-difluoromethylornithine (DFMO), may enhance ovarian tumor sensitivity to the PARP inhibitor, rucaparib. In HR-competent ovarian cancer cell lines with varying sensitivities to rucaparib, we show that co-treatment with DFMO increases the sensitivity of ovarian cancer cells to rucaparib. Immunofluorescence assays demonstrated that, in the presence of hydrogen peroxide-induced DNA damage, DFMO strongly inhibits PARylation, increases DNA damage accumulation, and reduces cell viability in both HR-competent and deficient cell lines. In vitro viability assays show that DFMO and rucaparib cotreatment significantly enhances the cytotoxicity of the chemotherapeutic agent, cisplatin. These results suggest that DFMO may be a useful adjunct chemotherapeutic to improve the anti-tumor efficacy of PARP inhibitors in treating ovarian cancer.<\/jats:p>","DOI":"10.3390\/medsci10020028","type":"journal-article","created":{"date-parts":[[2022,5,28]],"date-time":"2022-05-28T01:40:45Z","timestamp":1653702045000},"page":"28","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Difluoromethylornithine (DFMO) Enhances the Cytotoxicity of PARP Inhibition in Ovarian Cancer Cells"],"prefix":"10.3390","volume":"10","author":[{"given":"Olivia","family":"El Naggar","sequence":"first","affiliation":[{"name":"Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4549-0798","authenticated-orcid":false,"given":"Brenna","family":"Doyle","sequence":"additional","affiliation":[{"name":"Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelsey","family":"Mariner","sequence":"additional","affiliation":[{"name":"Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan K.","family":"Gilmour","sequence":"additional","affiliation":[{"name":"Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"284","DOI":"10.3322\/caac.21456","article-title":"Ovarian cancer statistics, 2018","volume":"68","author":"Torre","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1093\/annonc\/mds203","article-title":"The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane\/platinum-based therapy","volume":"23","author":"Hanker","year":"2012","journal-title":"Ann. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"626","DOI":"10.3332\/ecancer.2016.626","article-title":"Targeted agents in epithelial ovarian cancer: Review on emerging therapies and future developments","volume":"10","author":"Lokadasan","year":"2016","journal-title":"Ecancermedicalscience"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1056\/NEJMra041842","article-title":"Cancer of the ovary","volume":"351","author":"Cannistra","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7265","DOI":"10.1038\/sj.onc.1206933","article-title":"Cisplatin: Mode of cytotoxic action and molecular basis of resistance","volume":"22","author":"Siddik","year":"2003","journal-title":"Oncogene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1200\/JCO.2011.39.8545","article-title":"BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: A report from the Australian Ovarian Cancer Study Group","volume":"30","author":"Alsop","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3570","DOI":"10.1200\/JCO.2009.27.2997","article-title":"Somatic Mutations in BRCA1 and BRCA2 Could Expand the Number of Patients That Benefit from Poly (ADP Ribose) Polymerase Inhibitors in Ovarian Cancer","volume":"28","author":"Hennessy","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1006\/jmbi.2001.4564","article-title":"DNA double-strand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells","volume":"307","author":"Arnaudeau","year":"2001","journal-title":"J. Mol. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1093\/annonc\/mdw142","article-title":"BRCA somatic mutations and epigenetic BRCA modifications in serous ovarian cancer","volume":"27","author":"Moschetta","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Research Network (2011). Integrated genomic analyses of ovarian carcinoma. Nature, 474, 609\u2013615.","DOI":"10.1038\/nature10166"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1038\/nrc1457","article-title":"Hallmarks of \u2018BRCAness\u2019 in sporadic cancers","volume":"4","author":"Turner","year":"2004","journal-title":"Nat. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1042\/bj3420249","article-title":"Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions","volume":"342","author":"Desnoyers","year":"1999","journal-title":"Biochem. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nrc2812","article-title":"PARP inhibition: PARP1 and beyond","volume":"10","author":"Rouleau","year":"2010","journal-title":"Nat. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S1470-2045(16)30559-9","article-title":"Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): An international, multicentre, open-label, phase 2 trial","volume":"18","author":"Swisher","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3785","DOI":"10.1200\/JCO.2008.16.0812","article-title":"A Synthetic Lethal Therapeutic Approach: Poly(ADP) Ribose Polymerase Inhibitors for the Treatment of Cancers Deficient in DNA Double-Strand Break Repair","volume":"26","author":"Ashworth","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3389\/fonc.2014.00034","article-title":"Reversing Platinum Resistance in High-Grade Serous Ovarian Carcinoma: Targeting BRCA and the Homologous Recombination System","volume":"4","author":"Wiedemeyer","year":"2014","journal-title":"Front. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1200\/JCO.2014.56.2728","article-title":"Olaparib monotherapy in patients with advanced cancer and a germline BRCA1\/2 mutation","volume":"33","author":"Kaufman","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1056\/NEJMoa1105535","article-title":"Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer","volume":"366","author":"Ledermann","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1002\/iub.230","article-title":"Mammalian polyamine metabolism and function","volume":"61","author":"Pegg","year":"2009","journal-title":"IUBMB Life"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1038\/nrc1454","article-title":"Polyamines and cancer: Old molecules, new understanding","volume":"4","author":"Gerner","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_21","first-page":"2748","article-title":"Ornithine decarboxylase induction in transformation by H-Ras and RhoA","volume":"58","author":"Shantz","year":"1998","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7804","DOI":"10.1073\/pnas.90.16.7804","article-title":"The ornithine decarboxylase gene is a transcriptional target of c-Myc","volume":"90","author":"Packham","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1007\/s00726-013-1550-9","article-title":"Chromatin remodeling by polyamines and polyamine analogs","volume":"46","author":"Pasini","year":"2013","journal-title":"Amino Acids"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1021\/bi0301791","article-title":"Regulation of the Enzymatic Catalysis of Poly(ADP-ribose) Polymerase by dsDNA, Polyamines, Mg2+, Ca2+, Histones H1 and H3, and ATP","volume":"43","author":"Kun","year":"2003","journal-title":"Biochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1093\/oxfordjournals.jbchem.a133896","article-title":"Effect of polyamines on two types of reaction of purified poly(ADP-ribose) polymerase","volume":"91","author":"Tanaka","year":"1982","journal-title":"J. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41467-018-08011-1","article-title":"Promotion of homology-directed DNA repair by polyamines","volume":"10","author":"Lee","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1158\/1535-7163.MCT-12-0813","article-title":"Therapeutic Potential of the Poly(ADP-ribose) Polymerase Inhibitor Rucaparib for the Treatment of Sporadic Human Ovarian Cancer","volume":"12","author":"Ihnen","year":"2013","journal-title":"Mol. Cancer Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1097\/MPA.0b013e31821ae25b","article-title":"Increased Expression of DNA Repair Genes in Invasive Human Pancreatic Cancer Cells","volume":"40","author":"Mathews","year":"2011","journal-title":"Pancreas"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"R31","DOI":"10.1186\/bcr2583","article-title":"Senescence evasion by MCF-7 human breast tumor-initiating cells","volume":"12","author":"Mackey","year":"2010","journal-title":"Breast Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1158\/1078-0432.CCR-15-1348","article-title":"RAD51 Mediates Resistance of Cancer Stem Cells to PARP Inhibition in Triple-Negative Breast Cancer","volume":"23","author":"Liu","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/onc.2017.341","article-title":"A slow-cycling subpopulation of melanoma cells with highly invasive properties","volume":"37","author":"Perego","year":"2017","journal-title":"Oncogene"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/0167-4781(84)90123-4","article-title":"In vivo formation of single-strand breaks in DNA by hydrogen peroxide is mediated by the Haber-Weiss reaction","volume":"781","author":"Filho","year":"1984","journal-title":"Biochim. Biophys. Acta-Gene Struct. Expr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"479","DOI":"10.3109\/10715761003667554","article-title":"Reactive oxygen species in cancer","volume":"44","author":"Liou","year":"2010","journal-title":"Free Radic. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/leu.2010.6","article-title":"GammaH2AX: A sensitive molecular marker of DNA damage and repair","volume":"24","author":"Mah","year":"2010","journal-title":"Leukemia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"42462","DOI":"10.1074\/jbc.C100466200","article-title":"ATM Phosphorylates Histone H2AX in Response to DNA Double-strand Breaks","volume":"276","author":"Burma","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"47759","DOI":"10.1074\/jbc.C100569200","article-title":"Histone H2AX Is Phosphorylated in an ATR-dependent Manner in Response to Replicational Stress","volume":"276","author":"Ward","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"920161","DOI":"10.4061\/2010\/920161","article-title":"H2AX Phosphorylation: Its Role in DNA Damage Response and Cancer Therapy","volume":"2010","author":"Podhorecka","year":"2010","journal-title":"J. Nucleic Acids"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1093\/jmcb\/mju045","article-title":"CHK2 kinase in the DNA damage response and beyond","volume":"6","author":"Zannini","year":"2014","journal-title":"J. Mol. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1038\/s41388-018-0506-7","article-title":"CHK2-mediated regulation of PARP1 in oxidative DNA damage response","volume":"38","author":"Hsu","year":"2018","journal-title":"Oncogene"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1093\/carcin\/bgv079","article-title":"Initiation of the ATM-Chk2 DNA damage response through the base excision repair pathway","volume":"36","author":"Chou","year":"2015","journal-title":"Carcinogenesis"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"36163","DOI":"10.1074\/jbc.M303795200","article-title":"Autophosphorylation of Checkpoint Kinase 2 at Serine 516 Is Required for Radiation-induced Apoptosis","volume":"278","author":"Wu","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"102664","DOI":"10.1016\/j.dnarep.2019.102664","article-title":"XRCC1 protein; Form and function","volume":"81","author":"Caldecott","year":"2019","journal-title":"DNA Repair"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3140","DOI":"10.1038\/emboj.2008.229","article-title":"Chk2-dependent phosphorylation of XRCC1 in the DNA damage response promotes base excision repair","volume":"27","author":"Chou","year":"2008","journal-title":"EMBO J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"240","DOI":"10.3389\/fonc.2015.00240","article-title":"Preventing Damage Limitation: Targeting DNA-PKcs and DNA Double-Strand Break Repair Pathways for Ovarian Cancer Therapy","volume":"5","author":"Dungl","year":"2015","journal-title":"Front. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.molonc.2012.12.007","article-title":"BRCA1\/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation","volume":"7","author":"Stordal","year":"2013","journal-title":"Mol. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1073\/pnas.1908003117","article-title":"RAP80 and BRCA1 PARsylation protect chromosome integrity by preventing retention of BRCA1-B\/C complexes in DNA repair foci","volume":"117","author":"Vohhodina","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/35004614","article-title":"hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response","volume":"404","author":"Lee","year":"2000","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3977","DOI":"10.1038\/onc.2008.17","article-title":"The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage","volume":"27","author":"Bahassi","year":"2008","journal-title":"Oncogene"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.dnarep.2018.08.021","article-title":"Mechanisms of PARP inhibitor sensitivity and resistance","volume":"71","year":"2018","journal-title":"DNA Repair"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1038\/nature06633","article-title":"Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers","volume":"451","author":"Sakai","year":"2008","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1002\/(SICI)1097-4644(20000601)77:3<345::AID-JCB1>3.0.CO;2-P","article-title":"High levels of intracellular polyamines promote histone acetyltransferase activity resulting in chromatin hyperacetylation","volume":"77","author":"Hobbs","year":"2000","journal-title":"J. Cell. Biochem."},{"key":"ref_52","first-page":"67","article-title":"Deregulation of polyamine biosynthesis alters intrinsic histone acetyltransferase and deacetylase activities in murine skin and tumors","volume":"62","author":"Hobbs","year":"2002","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/S0014-4827(03)00352-5","article-title":"Elevated levels of polyamines alter chromatin in murine skin and tumors without global changes in nucleosome acetylation","volume":"290","author":"Hobbs","year":"2003","journal-title":"Exp. Cell Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"8116","DOI":"10.1158\/0008-5472.CAN-06-0359","article-title":"Tip60 Protein Isoforms and Altered Function in Skin and Tumors that Overexpress Ornithine Decarboxylase","volume":"66","author":"Hobbs","year":"2006","journal-title":"Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1002\/mc.20350","article-title":"Polyamine-mediated regulation of protein acetylation in murine skin and tumors","volume":"46","author":"Wei","year":"2007","journal-title":"Mol. Carcinog."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1038\/nsmb.1941","article-title":"Transcriptional regulation of BRCA1 expression by a metabolic switch","volume":"17","author":"Di","year":"2010","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13048-015-0140-8","article-title":"A metabolomic approach to identifying platinum resistance in ovarian cancer","volume":"8","author":"Poisson","year":"2015","journal-title":"J. Ovarian Res."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"von Stechow, L., Ruiz-Aracama, A., van de Water, B., Peijnenburg, A., Danen, E., and Lommen, A. (2013). Identification of cisplatin-regulated metabolic pathways in pluripotent stem cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076476"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s00726-009-0408-7","article-title":"Functional significance of eIF5A and its hypusine modification in eukaryotes","volume":"38","author":"Park","year":"2009","journal-title":"Amino Acids"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5755","DOI":"10.1038\/s41467-020-19602-2","article-title":"A translational program that suppresses metabolism to shield the genome","volume":"11","author":"Balukoff","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.ccr.2013.05.003","article-title":"Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells","volume":"23","author":"Roesch","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.cmet.2017.09.009","article-title":"MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation","volume":"26","author":"Lee","year":"2017","journal-title":"Cell Metab."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.biocel.2005.07.004","article-title":"Anti-oxidant activity of spermine and spermidine re-evaluated with oxidizing systems involving iron and copper ions","volume":"38","author":"Mozdzan","year":"2006","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1158\/0008-5472.CAN-17-1494","article-title":"Synthetic Lethality of PARP Inhibitors in Combination with MYC Blockade Is Independent of BRCA Status in Triple-Negative Breast Cancer","volume":"78","author":"Carey","year":"2017","journal-title":"Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.bcp.2019.06.012","article-title":"Therapeutic considerations of PARP in stem cell biology: Relevance in cancer and beyond","volume":"167","author":"Zeniou","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1158\/1541-7786.MCR-18-0594","article-title":"PARP Inhibition Induces Enrichment of DNA Repair\u2013Proficient CD133 and CD117 Positive Ovarian Cancer Stem Cells","volume":"17","author":"Bellio","year":"2018","journal-title":"Mol. Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"9658","DOI":"10.1158\/0008-5472.CAN-07-0290","article-title":"RAD51 Up-regulation Bypasses BRCA1 Function and Is a Common Feature of BRCA1-Deficient Breast Tumors","volume":"67","author":"Martin","year":"2007","journal-title":"Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"eaal5148","DOI":"10.1126\/scitranslmed.aal5148","article-title":"Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers","volume":"9","author":"Sun","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1136\/ijgc-00009577-200509000-00026","article-title":"Overexpression of cyclin D1 and c-Myc gene products in human primary epithelial ovarian cancer","volume":"15","author":"Chen","year":"2005","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1172\/JCI71180","article-title":"MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis","volume":"124","author":"Terunuma","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"5364","DOI":"10.1158\/0008-5472.CAN-08-4135","article-title":"A Novel Lung Metastasis Signature Links Wnt Signaling with Cancer Cell Self-Renewal and Epithelial-Mesenchymal Transition in Basal-like Breast Cancer","volume":"69","author":"DiMeo","year":"2009","journal-title":"Cancer Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6641","DOI":"10.1158\/0008-5472.CAN-16-3452","article-title":"MYC Inhibition Depletes Cancer Stem-like Cells in Triple-Negative Breast Cancer","volume":"77","author":"Yang","year":"2017","journal-title":"Cancer Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"7048","DOI":"10.1158\/0008-5472.CAN-14-1470","article-title":"Targeting the MYC and PI3K Pathways Eliminates Leukemia-Initiating Cells in T-cell Acute Lymphoblastic Leukemia","volume":"74","author":"Schubbert","year":"2014","journal-title":"Cancer Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"5903","DOI":"10.1158\/0008-5472.CAN-14-0527","article-title":"MYC Activates Stem-like Cell Potential in Hepatocarcinoma by a p53-Dependent Mechanism","volume":"74","author":"Akita","year":"2014","journal-title":"Cancer Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6816","DOI":"10.1158\/0008-5472.CAN-13-0615","article-title":"RNAi-Mediated Silencing of Myc Transcription Inhibits Stem-like Cell Maintenance and Tumorigenicity in Prostate Cancer","volume":"73","author":"Civenni","year":"2013","journal-title":"Cancer Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.1158\/1535-7163.MCT-14-0801","article-title":"Targeting c-MYC in Platinum-Resistant Ovarian Cancer","volume":"14","author":"Mangala","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"ra19","DOI":"10.1126\/scisignal.2001556","article-title":"c-MYC Suppresses BIN1 to Release Poly(ADP-Ribose) Polymerase 1: A Mechanism by Which Cancer Cells Acquire Cisplatin Resistance","volume":"4","author":"Pyndiah","year":"2011","journal-title":"Sci. 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