title: Different apoptotic effects of [Pt(O,O'-acac)(γ-acac)(DMS)] and cisplatin on normal and cancerous human epithelial breast cells in primary culture.
abstract: OBJECTIVE
  The aim of this study was to determine whether [platinum (Pt)(O,O'-acetylacetonate (acac))(γ-acac)(dimethylsulphide (DMS))] is differentially cytotoxic in normal and cancer cells, and to measure comparative levels of cytotoxicity compared with cisplatin in the same cells.
  
  
  METHODS
  We performed experiments on cancerous and normal epithelial breast cells in primary culture obtained from the same patients. The apoptotic effects [Pt(O,O'-acac)(γ-acac)(DMS)] and cisplatin in cancerous and normal breast cells were compared.
  
  
  RESULTS
  Cancer cells were more sensitive to [Pt(O,O'-acac)(γ-acac)(DMS)] (IC50 = 5.22 ± 1.2 μmol·L(-1)) than normal cells (IC50 = 116.9 ± 8.8 μmol·L(-1)). However, the difference was less strong when cisplatin was used (IC50 = 96.0 ± 6.9 and 61.9 ± 6.1 μmol·L(-1) for cancer and normal cells respectively). Both compounds caused reactive oxygen species (ROS) production with different mechanisms: [Pt(O,O'-acac)(γ-acac)(DMS)] quickly activated NAD(P)H oxidase while cisplatin caused a slower formation of mitochondrial ROS. Cisplatin and [Pt(O,O'-acac)(γ-acac)(DMS)] caused activation of caspases, proteolysis of PARP and modulation of Bcl-2, Bax and Bid. [Pt(O,O'-acac)(γ-acac)(DMS)] also caused leakage of cytochrome c from the mitochondria. Overall, these processes proceeded more quickly in cells treated with [Pt(O,O'-acac)(γ-acac)(DMS)] compared with cisplatin. [Pt(O,O'-acac)(γ-acac)(DMS)] effects were faster and quantitatively greater in cancer than in normal cells. [Pt(O,O'-acac)(γ-acac)(DMS)] caused a fast decrease of mitochondrial membrane potential, especially in cancer cells.
  
  
  CONCLUSIONS
  [Pt(O,O'-acac)(γ-acac)(DMS)] was specific to breast cancer cells in primary culture, and this observation makes this compound potentially more interesting than cisplatin.
authors.affiliation: Cell Physiology Lab, Dipartimento di Scienze e Tecnologie Biologiche e Ambientali (Di.S.Te.B.A.), Universita' del Salento, Lecce, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Vetrugno
authors.forename: Antonella
authors.initials: A
authors.lastname: Muscella
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Fanizzi
authors.forename: Luca Giulio
authors.initials: LG
authors.lastname: Cossa
authors.forename: Danilo
authors.initials: D
authors.lastname: Migoni
authors.forename: Sandra Angelica
authors.initials: SA
authors.lastname: De Pascali
authors.forename: Santo
authors.initials: S
authors.lastname: Marsigliante
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D010984:Platinum / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D009944:Organoplatinum Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; C527556:Pt(O,O'-acac)(gamma-acac)(DMS); D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D010984:Platinum; D002945:Cisplatin