title: A trans-platinum(II) complex induces apoptosis in cancer stem cells of breast cancer.
abstract: Recent 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 (0-100μM). 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.
authors.affiliation: Department of Biology, Faculty of Arts and Sciences, Uludag University, 16059 Bursa, Turkey.
authors.forename: Nazlihan
authors.initials: N
authors.lastname: Aztopal
authors.affiliation: Department of Biology, Faculty of Arts and Sciences, Uludag University, 16059 Bursa, Turkey.
authors.forename: Didem
authors.initials: D
authors.lastname: Karakas
authors.affiliation: Department of Biology, Faculty of Arts and Sciences, Uludag University, 16059 Bursa, Turkey.
authors.forename: Buse
authors.initials: B
authors.lastname: Cevatemre
authors.affiliation: Department of Biology, Faculty of Arts and Sciences, Uludag University, 16059 Bursa, Turkey. Electronic address: ferdaoz@uludag.edu.tr.
authors.forename: Ferda
authors.initials: F
authors.lastname: Ari
authors.affiliation: Department of Chemistry, Faculty of Arts and Sciences, Uludag University, 16059 Bursa, Turkey.
authors.forename: Ceyda
authors.initials: C
authors.lastname: Icsel
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milan, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Daidone
authors.affiliation: Department of Medical Biochemistry, School of Medicine, Istinye University, Istanbul, Turkey.
authors.forename: Engin
authors.initials: E
authors.lastname: Ulukaya
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D061945:Caspase Inhibitors / Q000494:pharmacology; D000066673:Cell Self Renewal / Q000187:drug effects; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009336:Necrosis; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D007093:Imidazoles; D007211:Indoles; D050814:Octamer Transcription Factor-3; D009842:Oligopeptides; D009944:Organoplatinum Compounds; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; C000611061:dichloridobis(2-(2-hydroxyethyl)pyridine)platinum(II); C507699:necrostatin-1
keywords: Anti-growth effect; Apoptosis; Breast cancer stem cells; Necroptosis; Platinum