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

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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.

KEY 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 AND IMPLICATIONS:

[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: Carla Vetrugno, Antonella Muscella, Francesco Paolo Fanizzi, Luca Giulio Cossa, Danilo Migoni, Sandra Angelica De Pascali, Santo Marsigliante
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 171 Issue 22 Pg. 5139-53 (Nov 2014) ISSN: 1476-5381 [Electronic] England
• PMID: 24990093 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The British Pharmacological Society.

Chemical References

• Antineoplastic Agents
• BAX protein, human
• Organoplatinum Compounds
• Proto-Oncogene Proteins c-bcl-2
• Pt(O,O'-acac)(gamma-acac)(DMS)
• Reactive Oxygen Species
• bcl-2-Associated X Protein
• Platinum
• Cisplatin

Topics

• Antineoplastic Agents (pharmacokinetics, pharmacology)
• Apoptosis (drug effects)
• Breast (cytology)
• Breast Neoplasms (drug therapy, metabolism)
• Carcinoma, Ductal, Breast (drug therapy, metabolism)
• Cell Survival (drug effects)
• Cells, Cultured
• Cisplatin (pharmacokinetics, pharmacology)
• Epithelial Cells (drug effects, metabolism)
• Female
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Organoplatinum Compounds (pharmacokinetics, pharmacology)
• Platinum (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Reactive Oxygen Species (metabolism)
• Tumor Cells, Cultured
• bcl-2-Associated X Protein (metabolism)