Eskiler, Gamze Güney2022-12-282022-12-282018-11-15Eskiler, G. G. vd. (2018). ''Synthetically lethal BMN 673 (Talazoparib) loaded solid lipid nanoparticles for BRCA1 mutant triple negative breast cancer''. Pharmaceutical Research, 35(11).0724-87411573-904Xhttps://doi.org/10.1007/s11095-018-2502-6link.springer.com/article/10.1007/s11095-018-2502-6http://hdl.handle.net/11452/30141Purpose The purpose of the study was to produce BMN 673 loaded solid lipid nanoparticles (SLNs) to improve its therapeutic index, to minimize toxicity and to overcome homologous recombination (HR)-mediated resistance.MethodsFirstly, BMN 673-SLNs were characterized using Nano Zeta Sizer. After treatment with different concentrations of BMN 673 and BMN 673-SLNs, cell viability of HCC1937((BRCA1-/-)), HCC1937-R (BMN 673-resistant) TNBC and MCF-10A normal human mammary breast epithelial cell line was analyzed by WST-1 assay. In an attempt to assess the therapeutic synthetic lethality efficacy of SLNs formulation, cell cycle arrest, DNA damage, mRNA expression levels of PARP1, H2AFX, RAD51 and BRCA1 gene were investigated. Then, PARP, ?H2AX, RAD51 and BRCA1 protein expression and nuclear localization were analyzed by western blot and immunofluorescence analysis.ResultsWhen compared with BMN 673, BMN 673-SLNs showed remarkably a decrease in HCC1937 and HCC1937-R cells with less damage to MCF-10A cells. BMN 673-SLNs significantly induced toxicity through double-stranded DNA breaks, G2/M cell cycle arrest and PARP cleavage in TNBC cells. Additionally, BMN 673-resistance was mediated by miR-107, miR-193b and miR-1255b targeting BRCA1 and RAD51 in HCC1937 and HCC1937-R cells. However, BMN 673-SLNs treatment could overcome HR-mediated resistance in TNBC cells.Conclusions As a result, our findings suggest that SLNs formulation strongly provides a synthetic lethal therapeutic potential in BRCA1 mutated sensitive and resistant TNBC cells.eninfo:eu-repo/semantics/closedAccessChemistryPharmacology & pharmacyBMN 673 (Talozoparib)Poly ADP ribose polymerase (PARP) inhibitorsSolid lipid nanoparticles (SLNs)Synthetic lethalityTriple negative breast cancer (TNBC)Poly(ADP-ribose) polymerase-1/2 inhibitorParp inhibitorDNA-repairVivo sensitivityHighly polentIn-vitroResistanceDeficientMutationsTherapyAntineoplastic agentsBRCA1 proteinCell cycle checkpointsCell line, tumorDNA breaks, double-strandedDrug carriersHumansLipidsMutationNanoparticlesPhthalazinesPoly(ADP-ribose) polymerase inhibitorsTriple negative breast neoplasmsArticle0004456556000042-s2.0-85053843953351130255456Chemistry, multidisciplinaryPharmacology & pharmacyOlaparib; Ovarian Neoplasms; Homologous RecombinationBRCA1 proteinHistone H2AXNicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferaseNicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1Nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitorRad51 proteinSolid lipid nanoparticleTalazoparibAntineoplastic agentBRCA1 proteinBRCA1 protein, humanDrug carrierLipidNanoparticleNicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitorPhthalazine derivativeTalazoparibAntineoplastic activityApoptosisArticleCell cycle arrestCell cycle M phaseCell populationCell viabilityCytotoxicityDispersityDNA damageDouble stranded DNA breakG2 phase cell cycle checkpointGene controlGene expressionGene mutationHCC1937 cell lineHCC1937-R cell lineHomologous recombinationHumanHuman cellImmunofluorescenceImmunofluorescence microscopyIn vitro studyLoading drug doseMCF-10A cell lineMRNA expression levelParticle sizePolymerase chain reactionPriority journalProtein expressionReverse transcription polymerase chain reactionTherapeutic indexTherapyWestern blottingWST-1 assayZeta potentialCell cycle checkpointChemistryDrug effectGeneticsMutationTriple negative breast cancerTumor cell line