Different apoptotic effects of [Pt(O, O %26apos;-acac)(gamma-acac)(DMS)] and cisplatin on normal and cancerous human epithelial breast cells in primary culture

作者：Vetrugno Carla; Muscella Antonella; Fanizzi Francesco Paolo; Cossa Luca Giulio; Migoni Danilo; De Pascali Sandra Angelica; Marsigliante Santo^*

来源：British Journal of Pharmacology, 2014, 171(22): 5139-5153.

DOI：10.1111/bph.12831

Background and PurposeThe aim of this study was to determine whether [platinum (Pt)(O,O-acetylacetonate (acac))(-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. %26lt;br%26gt;Experimental ApproachWe performed experiments on cancerous and normal epithelial breast cells in primary culture obtained from the same patients. The apoptotic effects [Pt(O,O-acac)(-acac)(DMS)] and cisplatin in cancerous and normal breast cells were compared. %26lt;br%26gt;Key ResultsCancer cells were more sensitive to [Pt(O,O-acac)(-acac)(DMS)] (IC50 = 5.22 1.2molL(-1)) than normal cells (IC50 = 116.9 +/- 8.8molL(-1)). However, the difference was less strong when cisplatin was used (IC50 = 96.0 +/- 6.9 and 61.9 +/- 6.1molL(-1) for cancer and normal cells respectively). Both compounds caused reactive oxygen species (ROS) production with different mechanisms: [Pt(O,O-acac)(-acac)(DMS)] quickly activated NAD(P)H oxidase while cisplatin caused a slower formation of mitochondrial ROS. Cisplatin and [Pt(O,O-acac)(-acac)(DMS)] caused activation of caspases, proteolysis of PARP and modulation of Bcl-2, Bax and Bid. [Pt(O,O-acac)(-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)(-acac)(DMS)] compared with cisplatin. [Pt(O,O-acac)(-acac)(DMS)] effects were faster and quantitatively greater in cancer than in normal cells. [Pt(O,O-acac)(-acac)(DMS)] caused a fast decrease of mitochondrial membrane potential, especially in cancer cells. %26lt;br%26gt;Conclusions and Implications[Pt(O,O-acac)(-acac)(DMS)] was specific to breast cancer cells in primary culture, and this observation makes this compound potentially more interesting than cisplatin.

• 出版日期2014-11