Featured Publications
Poly (ADP-ribose) polymerase inhibitors
Ratner ES, Sartorelli AC, Lin ZP. Poly (ADP-ribose) polymerase inhibitors. Current Opinion In Oncology 2012, 24: 564-571. PMID: 22759740, PMCID: PMC3799945, DOI: 10.1097/cco.0b013e3283564230.Peer-Reviewed Original ResearchConceptsEpithelial ovarian cancerOvarian cancerOverall survivalEOC patientsPARP inhibitorsBRCA mutationsHereditary epithelial ovarian cancerLower chemotherapy response rateDNA repair defectsDeleterious BRCA1/2 mutationsPlatinum-based chemotherapyRecurrence-free survivalChemotherapy response rateRecent clinical trialsPoor overall survivalNew treatment optionsShorter survival timeSporadic epithelial ovarian cancerPoly (ADP-ribose) polymerasePoly (ADP-ribose) polymerase (PARP) inhibitorsEffect of cisplatinPARP inhibitor olaparibRecurrent diseaseClinical outcomesTherapeutic challengeIn 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 malignanciesGene expression of non-homologous end-joining pathways in the prognosis of ovarian cancer
Lavi E, Lin Z, Ratner E. Gene expression of non-homologous end-joining pathways in the prognosis of ovarian cancer. IScience 2023, 26: 107934. PMID: 37810216, PMCID: PMC10558711, DOI: 10.1016/j.isci.2023.107934.Peer-Reviewed Original ResearchOvarian cancer patientsClinical outcomesCancer patientsDisease progressionOvarian cancerFive-year overall survival rateOverall survival rateDeadliest gynecologic malignancyLogistic regression modelsGynecologic malignanciesPatient survivalPrognostic biomarkerSurvival rateSample t-testPatientsT-testCancerProgressionRegression modelsOutcomesExpression profilesGene expressionMalignancyPrognosisRecurrencePredictive modeling of gene mutations for the survival outcomes of epithelial ovarian cancer patients
C. M, Lavi E, Altwerger G, Lin Z, Ratner E. Predictive modeling of gene mutations for the survival outcomes of epithelial ovarian cancer patients. PLOS ONE 2024, 19: e0305273. PMID: 38976671, PMCID: PMC11230535, DOI: 10.1371/journal.pone.0305273.Peer-Reviewed Original ResearchConceptsEpithelial ovarian cancerEpithelial ovarian cancer patientsEpithelial ovarian cancer casesGene mutation signaturesPlatinum-based chemotherapyThe Cancer Genome AtlasResponse to treatmentOverall survivalGene mutationsMutational signaturesHomologous recombinationSurvival outcomesIncreased sensitivity to platinum-based chemotherapySensitivity to platinum-based chemotherapyAssociated with increased chemoresistanceResistance to platinum-based chemotherapySurvival timeSurvival rateFavorable response to treatmentPlatinum-induced DNA damageKaplan-Meier survival analysisPrediction of survival outcomesOvarian cancer patientsOverall survival ratePrediction of treatment outcome
2023
Transforming Growth Factor Beta and Epithelial to Mesenchymal Transition Alter Homologous Recombination Repair Gene Expression and Sensitize BRCA Wild-Type Ovarian Cancer Cells to Olaparib
Roberts C, Rojas-Alexandre M, Hanna R, Lin Z, Ratner E. Transforming Growth Factor Beta and Epithelial to Mesenchymal Transition Alter Homologous Recombination Repair Gene Expression and Sensitize BRCA Wild-Type Ovarian Cancer Cells to Olaparib. Cancers 2023, 15: 3919. PMID: 37568736, PMCID: PMC10417836, DOI: 10.3390/cancers15153919.Peer-Reviewed Original ResearchEpithelial ovarian cancerRepair gene expressionPARP inhibitorsHomologous recombinationGene expressionDNA repair gene expressionCancer cellsLethal gynecologic malignancyDrug-resistant recurrenceDownregulation of genesOvarian cancer cellsGrowth factor betaWild-type cancer cellsDose-dependent mannerDNA repair genesGynecologic malignanciesMesenchymal tumorsOvarian tumorsEpithelial cell lineOvarian cancerMetastatic spreadClinical utilityEOC cellsFunctions of EMTFactor beta
2020
Flow Cytometric Analyses of p53-Mediated Cell Cycle Arrest and Apoptosis in Cancer Cells
Al Zouabi NN, Roberts CM, Lin ZP, Ratner ES. Flow Cytometric Analyses of p53-Mediated Cell Cycle Arrest and Apoptosis in Cancer Cells. Methods In Molecular Biology 2020, 2255: 43-53. PMID: 34033093, DOI: 10.1007/978-1-0716-1162-3_5.Peer-Reviewed Original ResearchConceptsGene of interestCell cycle arrestCycle arrestCell typesDNA damaging agentsP53-mediated cell cycle arrestCell cycle progressionTumor suppressor p53Cellular contextEctopic expressionExogenous stressCell cycle distributionDamaging agentsCycle progressionTumor suppressorSuppressor p53Stable expressionPhenotypic analysisCell survivalCell deathGenomic damageP53 functionGenesEnvironmental insultsCycle distribution
2016
MK-2206 sensitizes BRCA-deficient epithelial ovarian adenocarcinoma to cisplatin and olaparib
Whicker ME, Lin ZP, Hanna R, Sartorelli AC, Ratner ES. MK-2206 sensitizes BRCA-deficient epithelial ovarian adenocarcinoma to cisplatin and olaparib. BMC Cancer 2016, 16: 550. PMID: 27465688, PMCID: PMC4964088, DOI: 10.1186/s12885-016-2598-1.Peer-Reviewed Original ResearchMeSH KeywordsBRCA1 ProteinCarcinoma, Ovarian EpithelialCell Line, TumorCell SurvivalCisplatinDrug SynergismFemaleGene Expression Regulation, NeoplasticHeterocyclic Compounds, 3-RingHumansMutationNeoplasms, Glandular and EpithelialOvarian NeoplasmsPhosphorylationPhthalazinesPiperazinesProto-Oncogene Proteins c-aktConceptsEpithelial ovarian cancerOlaparib therapyOvarian adenocarcinomaPhase II trialGreater clinical responseSerous ovarian adenocarcinomaPhospho-AKT activityAgent-induced DNA damageAkt activityEpithelial ovarian adenocarcinomaII trialPeritoneal cancerClinical responseInhibition of AktPatient populationStrong synergismFallopian tubeOvarian cancerHomologous recombination repair pathwaySame patientChemosensitization agentsClinical investigationChemoresistant cellsPlatinum resistanceBRCA-deficient cellsTriapine 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
2014
p53 protein aggregation promotes platinum resistance in ovarian cancer
Yang-Hartwich Y, Soteras MG, Lin ZP, Holmberg J, Sumi N, Craveiro V, Liang M, Romanoff E, Bingham J, Garofalo F, Alvero A, Mor G. p53 protein aggregation promotes platinum resistance in ovarian cancer. Oncogene 2014, 34: 3605-3616. PMID: 25263447, DOI: 10.1038/onc.2014.296.Peer-Reviewed Original ResearchConceptsPro-apoptotic functionP53 aggregationProtein aggregationP53 aggregatesNormal transcriptional activationTwo-dimensional gel electrophoresisCancer cellsCancer cell survivalKey transcriptional factorGenetic mutationsHigh-grade serous ovarian carcinomaP53 inactivationP53 proteinStem cell propertiesCancer stem cell propertiesCellular homeostasisTranscriptional activationCancer stem cellsTranscriptional factorsTumor-initiating capacityP53 turnoverCell survivalHGSOC cellsStem cellsPotential therapeutic targetMK-2206 sensitizes BRCA2 mutant ovarian adenocarcinoma to cisplatin and poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitor therapy
Whicker M, Lin Z, Sartorelli A, Ratner E. MK-2206 sensitizes BRCA2 mutant ovarian adenocarcinoma to cisplatin and poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitor therapy. Gynecologic Oncology 2014, 133: 86-87. DOI: 10.1016/j.ygyno.2014.03.231.Peer-Reviewed Original Research
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
2007
Disruption of cAMP and Prostaglandin E2 Transport by Multidrug Resistance Protein 4 Deficiency Alters cAMP-Mediated Signaling and Nociceptive Response
Lin ZP, Zhu YL, Johnson DR, Rice KP, Nottoli T, Hains BC, McGrath J, Waxman SG, Sartorelli AC. Disruption of cAMP and Prostaglandin E2 Transport by Multidrug Resistance Protein 4 Deficiency Alters cAMP-Mediated Signaling and Nociceptive Response. Molecular Pharmacology 2007, 73: 243-251. PMID: 17959714, PMCID: PMC2780335, DOI: 10.1124/mol.107.039594.Peer-Reviewed Original ResearchConceptsNociceptive responsesPG synthesisInflammatory nociceptive responsesInflammatory pain thresholdWild-type miceCyclooxygenase-2 expressionMrp4 knockout miceMultidrug resistance protein 4Accumulation of intracellularMEF cellsMRP4 knockdownNucleotide agentsPain thresholdDisruptions of cAMPPGE metabolitePG levelsEnergy-dependent effluxProtein 4MiceMRP4PG transportIntracellular levelsProstaglandinsATP-binding cassette (ABC) familyPronounced reductionAtaxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis
Eaton JS, Lin ZP, Sartorelli AC, Bonawitz ND, Shadel GS. Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis. Journal Of Clinical Investigation 2007, 117: 2723-2734. PMID: 17786248, PMCID: PMC1952633, DOI: 10.1172/jci31604.Peer-Reviewed Original ResearchMeSH KeywordsAtaxia Telangiectasia Mutated ProteinsCell CycleCell Cycle ProteinsCells, CulturedDNA-Binding ProteinsDNA, MitochondrialGene DosageGene Expression Regulation, EnzymologicHomeostasisHumansMitochondriaMutationProtein BiosynthesisProtein Serine-Threonine KinasesProtein SubunitsReactive Oxygen SpeciesRibonucleotide ReductasesTumor Suppressor ProteinsUp-RegulationConceptsRibonucleotide reductaseMitochondrial homeostasisRNA interferenceNuclear DNA damage responseAtaxia telangiectasiaATM inhibitor KU-55933Disruption of ATMNormal growth conditionsDNA damage responseMitochondrial transcription factorWild-type fibroblastsCandidate disease lociMtDNA depletion syndromeMtDNA copy numberMitochondrial DNA depletionKU-55933P53R2 subunitsDamage responseTranscription factorsRate-limiting enzymeDe novo synthesisGlobal dysregulationT fibroblastsR1 subunitMitochondrial respiration
2006
Excess ribonucleotide reductase R2 subunits coordinate the S phase checkpoint to facilitate DNA damage repair and recovery from replication stress
Lin ZP, Belcourt MF, Carbone R, Eaton JS, Penketh PG, Shadel GS, Cory JG, Sartorelli AC. Excess ribonucleotide reductase R2 subunits coordinate the S phase checkpoint to facilitate DNA damage repair and recovery from replication stress. Biochemical Pharmacology 2006, 73: 760-772. PMID: 17188250, DOI: 10.1016/j.bcp.2006.11.014.Peer-Reviewed Original Research
2004
Resistance to purine and pyrimidine nucleoside and nucleobase analogs by the human MDR1 transfected murine leukemia cell line L1210/VMDRC.06
Zeng H, Lin ZP, Sartorelli AC. Resistance to purine and pyrimidine nucleoside and nucleobase analogs by the human MDR1 transfected murine leukemia cell line L1210/VMDRC.06. Biochemical Pharmacology 2004, 68: 911-921. PMID: 15294454, DOI: 10.1016/j.bcp.2004.06.004.Peer-Reviewed Original ResearchStable Suppression of the R2 Subunit of Ribonucleotide Reductase by R2-targeted Short Interference RNA Sensitizes p53(–/–) HCT-116 Colon Cancer Cells to DNA-damaging Agents and Ribonucleotide Reductase Inhibitors*
Lin ZP, Belcourt MF, Cory JG, Sartorelli AC. Stable Suppression of the R2 Subunit of Ribonucleotide Reductase by R2-targeted Short Interference RNA Sensitizes p53(–/–) HCT-116 Colon Cancer Cells to DNA-damaging Agents and Ribonucleotide Reductase Inhibitors*. Journal Of Biological Chemistry 2004, 279: 27030-27038. PMID: 15096505, DOI: 10.1074/jbc.m402056200.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsCell Line, TumorCell SurvivalCisplatinColonic NeoplasmsDeoxyribonucleotidesDNA DamageDown-RegulationDoxorubicinEnzyme InhibitorsEtoposideGene Expression Regulation, NeoplasticGene SilencingHumansHydroxyureaIntracellular Signaling Peptides and ProteinsProtein SubunitsProto-Oncogene ProteinsPyridinesRecombinant ProteinsRibonucleotide ReductasesRNA, Small InterferingThiosemicarbazonesTumor Suppressor Protein p53VincristineConceptsShort interference RNAR2 proteinRibonucleotide reductaseInterference RNADNA damageRNR inhibitorsHCT-116 cellsMammalian ribonucleotide reductaseDNA-damaging agent cisplatinCellular growth rateHCT-116 colon cancer cellsDNA-damaging agentsP53-dependent inductionColon cancer cellsHCT-116 human colon carcinoma cellsHuman colon carcinoma cellsDNA replicationEctopic expressionKnockdown cellsColon carcinoma cellsExpression vectorDeoxyribonucleoside diphosphatesStable expressionR2 subunitRibonucleotide reductase inhibitorAge-Related Differences in Vincristine Toxicity and Biodistribution in Wild-Type and Transporter-Deficient Mice
Muramatsu T, Johnson DR, Finch RA, Johnson LK, Leffert JJ, Lin ZP, Pizzorno G, Sartorelli AC. Age-Related Differences in Vincristine Toxicity and Biodistribution in Wild-Type and Transporter-Deficient Mice. Oncology Research Featuring Preclinical And Clinical Cancer Therapeutics 2004, 14: 331-343. PMID: 15301424, DOI: 10.3727/0965040041292387.Peer-Reviewed Original Research