Daidone, Maria G.Ulukaya, Engin2022-12-282022-12-282016-10-27Aztopal, N. vd. (2017). ''A trans-platinum(II) complex induces apoptosis in cancer stem cells of breast cancer''. Bioorganic and Medicinal Chemistry, 25(1), 269-274.0968-0896https://doi.org/10.1016/j.bmc.2016.10.032https://www.sciencedirect.com/science/article/pii/S096808961631077X1464-3391http://hdl.handle.net/11452/30128Recent accumulating evidence has supported the notion that tumors have hierarchically organized heterogeneous cell populations and a small subpopulation of cells, termed cancer stem cells (CSCs), are responsible for tumor initiation, maintenance as well as drug resistance. Therefore, targeting the CSCs along with the other cancer cells has been the most important topic during the last decade. In the present study, we evaluated the cytotoxic activity of trans-[PtCl2(2-hepy) 2] [2-hepy = 2-(2-hydroxyethyl) pyridine] complex and the mechanism of cell death in breast CSCs. Stemness markers, Oct-4 and Sox2, were determined in mammospheres by western blotting. Cytotoxicity was assessed using the ATP viability assay. Cell death was fluorescently visualized and further confirmed by flow cytometry as well as gene expression analysis. The Pt(II) complex significantly reduced the cell viability, prevented mammosphere formation and disrupted mammosphere structures in a dose-dependent manner (0100 lM). The mode of cell death was apoptosis and it was shown by the presence of caspase 3/7 activity, Annexin V-FITC positivity, decreased mitochondrial membrane potential and increased expressions of pro-apoptotic genes (TNFRSF10A and HRK). Interestingly, necroptosis was also observed by the evidence of increased MLKL expression. In conclusion, the Pt(II) complex seems to be a highly promising anticancer compound due to its promising cytotoxic activity on CSCs. Therefore, it deserves in vivo further studies for the proof-of-concept.eninfo:eu-repo/semantics/closedAccessBiochemistry & molecular biologyPharmacology & pharmacyChemistryAnti-growth effectApoptosisBreast cancer stem cellsNecroptosisPlatinumDinuclear platinum(II) complexStructural-characterizationTumor heterogeneityCytotoxic efficacyNecroptosisResistance2-(hydroxymethyl)pyridinePalladium(ii)InductionAnti-muc1Antineoplastic agentsApoptosisBreast neoplasmsCaspase inhibitorsCell self renewalFemaleHumansImidazolesIndolesMCF-7 cellsMembrane potential, mitochondrialNecrosisNeoplastic stem cellsOctamer transcription factor-3OligopeptidesOrganoplatinum compoundsSOXB1 transcription factorsArticle0003970528000292-s2.0-8500627214326927425127839660Biochemistry & molecular biologyChemistry, medicinalChemistry, organicAntineoplastic Activity; Prodrugs; TransplatinCarboplatinCaspase 3Caspase 7CisplatinOctamer transcription factor 4Platinum complexTranscription factor Sox2Antineoplastic agentBenzyloxycarbonyl-valyl-alanyl-aspartic acidCaspase inhibitorDichloridobis(2-(2-hydroxyethyl)pyridine)platinum(II)Imidazole derivativeIndole derivativeOctamer transcription factor 4OligopeptidePlatinum complexPOU5F1 protein, humanSOX2 protein, humantranscription factor Soxantineoplastic activityApoptosisArticleAssayATP viability assayBreast cancerBreast cellCancer inhibitionCancer stem cellCell deathCell viabilityControlled studyDose responseDrug cytotoxicityDrug mechanismEnzyme activityFlow cytometryGeneGene expressionHRK geneMitochondrial membrane potentialMLKL geneNecroptosisProtein expressionTNFRSF10A geneWestern blottingApoptosisBreast tumorCancer stem cellCell self-renewalDrug effectFemaleHumanMCF-7 cell lineMetabolismNecrosisPathologyNecrostatin-1IC50MammosphereIC90