Featured Publications
In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer
Lin ZP, Al Zouabi NN, Xu ML, Bowen NE, Wu TL, Lavi ES, Huang PH, Zhu YL, Kim B, Ratner ES. In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer. Scientific Reports 2021, 11: 8042. PMID: 33850183, PMCID: PMC8044145, DOI: 10.1038/s41598-021-87325-5.Peer-Reviewed Original ResearchConceptsEpithelial ovarian cancerSmall molecule inhibitorsPARP inhibitor resistancePARP inhibitorsBRCA mutationsOvarian cancerEOC cellsPoly ADP-ribose polymerase inhibitorsMolecule inhibitorsInhibitor resistanceADP-ribose polymerase inhibitorsTumor-bearing miceNovel small molecule inhibitorPARP inhibitor olaparibDefective homologous recombination (HR) repairEOC xenograftsClinical efficacySurvival timePutative small molecule inhibitorsInhibitor olaparibPolymerase inhibitorsHR repairInhibitorsCancerHomologous recombination repairTriapine Disrupts CtIP-Mediated Homologous Recombination Repair and Sensitizes Ovarian Cancer Cells to PARP and Topoisomerase Inhibitors
Lin ZP, Ratner ES, Whicker ME, Lee Y, Sartorelli AC. Triapine Disrupts CtIP-Mediated Homologous Recombination Repair and Sensitizes Ovarian Cancer Cells to PARP and Topoisomerase Inhibitors. Molecular Cancer Research 2014, 12: 381-393. PMID: 24413181, PMCID: PMC3962722, DOI: 10.1158/1541-7786.mcr-13-0480.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsCarcinoma, Ovarian EpithelialCarrier ProteinsCell Line, TumorDrug SynergismFemaleHumansNeoplasms, Glandular and EpithelialOvarian NeoplasmsPhthalazinesPiperazinesPoly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesPyridinesRecombination, GeneticRecombinational DNA RepairThiosemicarbazonesTopoisomerase InhibitorsTransfectionConceptsHomologous recombination repairEOC cellsCtIP phosphorylationRecombination repairDNA double-strand break resectionCyclin-dependent kinase activityTopoisomerase II inhibitor etoposidePhosphorylation of CtIPDouble-strand break resectionSmall molecule inhibitorsRPA32 phosphorylationBRCA1 interactionBRCA1 fociNbs1 complexMre11-Rad50Chk1 activationDSB resectionKinase activitySynthetic lethalityRAD51 fociOvarian cancer cellsInhibitor etoposideCell cycleRibonucleotide reductaseCtIPCombination of triapine, olaparib, and cediranib suppresses progression of BRCA-wild type and PARP inhibitor-resistant epithelial ovarian cancer
Lin ZP, Zhu YL, Lo YC, Moscarelli J, Xiong A, Korayem Y, Huang PH, Giri S, LoRusso P, Ratner ES. Combination of triapine, olaparib, and cediranib suppresses progression of BRCA-wild type and PARP inhibitor-resistant epithelial ovarian cancer. PLOS ONE 2018, 13: e0207399. PMID: 30444904, PMCID: PMC6239325, DOI: 10.1371/journal.pone.0207399.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Combined Chemotherapy ProtocolsBRCA1 ProteinBreast NeoplasmsCell Line, TumorDrug Resistance, NeoplasmFemaleHumansMice, NudeMice, SCIDPhthalazinesPiperazinesPoly(ADP-ribose) Polymerase InhibitorsPyridinesQuinazolinesThiosemicarbazonesXenograft Model Antitumor AssaysConceptsEpithelial ovarian cancerBRCA wild typeSCID-beige miceXenograft mouse modelOvarian cancerMouse modelSurvival timeNude micePARP inhibitorsEOC cell linesPARP inhibitor olaparibHomologous recombination repairCombination regimentsDefective homologous recombination (HR) repairEOC growthC tumorsSignificant prolongationBRCA mutationsAbdominal circumferenceEOC cellsSingle drugCediranibMarked suppressionTriple combinationTumor growthTargeting Cyclin-Dependent Kinases for Treatment of Gynecologic Cancers
Lin ZP, Zhu YL, Ratner ES. Targeting Cyclin-Dependent Kinases for Treatment of Gynecologic Cancers. Frontiers In Oncology 2018, 8: 303. PMID: 30135856, PMCID: PMC6092490, DOI: 10.3389/fonc.2018.00303.Peer-Reviewed Original ResearchCDK activityCell cycleDefective cell cycle regulationCyclin-dependent kinase activityCell cycle phase transitionCell cycle regulationCyclin-dependent kinasesNormal cell cycleHomologous recombination repairHallmarks of cancerTargeting Cyclin-Dependent KinasesSynthetic lethal approachCell cycle phasesSmall molecule inhibitorsGynecologic cancerCheckpoint activationPARP inhibitorsCycle regulationHR repairKinase activityRecombination repairDNA damaging modalitiesProtein targetsCDKMajor gynecologic malignancies
2016
Triapine potentiates platinum-based combination therapy by disruption of homologous recombination repair
Ratner ES, Zhu YL, Penketh PG, Berenblum J, Whicker ME, Huang PH, Lee Y, Ishiguro K, Zhu R, Sartorelli AC, Lin ZP. Triapine potentiates platinum-based combination therapy by disruption of homologous recombination repair. British Journal Of Cancer 2016, 114: 777-786. PMID: 26964031, PMCID: PMC4984868, DOI: 10.1038/bjc.2016.54.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsCarboplatinCarcinoma, Ovarian EpithelialCisplatinDoxorubicinDrug Resistance, NeoplasmFemaleHumansMiceMice, NudeNeoplasms, Glandular and EpithelialOvarian NeoplasmsPhthalazinesPiperazinesPolyethylene GlycolsRecombinational DNA RepairTumor Cells, CulturedXenograft Model Antitumor AssaysConceptsPlatinum-based combination therapyEpithelial ovarian cancerCombination therapyWild-type cancer cellsEOC cellsPlatinum-resistant epithelial ovarian cancerPlatinum resistanceHomologous recombination repairEOC tumor growthPlatinum-based combinationsXenograft tumor mouse modelCancer cellsWild-type BRCATumor growth delayTumor mouse modelClonogenic survival assaysClinical efficacyBRCA statusOvarian cancerMouse modelTumor growthGrowth delayHRR activityTherapySurvival assays
2011
Reduced Level of Ribonucleotide Reductase R2 Subunits Increases Dependence on Homologous Recombination Repair of Cisplatin-Induced DNA Damage
Lin ZP, Lee Y, Lin F, Belcourt MF, Li P, Cory JG, Glazer PM, Sartorelli AC. Reduced Level of Ribonucleotide Reductase R2 Subunits Increases Dependence on Homologous Recombination Repair of Cisplatin-Induced DNA Damage. Molecular Pharmacology 2011, 80: 1000-1012. PMID: 21875941, PMCID: PMC3228527, DOI: 10.1124/mol.111.074708.Peer-Reviewed Original ResearchConceptsNucleotide excision repairHomologous recombination repairR2 subunitRibonucleotide reductaseRecombination repairCell cycleP53-deficient human colon cancer cellsDNA damageS phaseDepletion of BRCA1Mammalian ribonucleotide reductaseSubsequent S phaseDouble-strand breaksHuman colon cancer cellsP53-deficient cancer cellsSingle-strand gapsCancer cellsCisplatin-induced DNA damageColon cancer cellsCisplatin-DNA lesionsGap-filling synthesisHeteromeric enzymeReplication stressΓ-H2AX inductionDNA repair