Different apoptotic effects of [Pt(O, O′‐acac)(γ‐acac)(DMS)] and cisplatin on normal and cancerous human epithelial breast cells in primary culture. (5th September 2014)

• Record Type: Journal Article
• Authors: Vetrugno, Carla; Muscella, Antonella; Fanizzi, Francesco Paolo; Cossa, Luca Giulio; Migoni, Danilo; De Pascali, Sandra Angelica; Marsigliante, Santo
• Is Part Of: British journal of pharmacology. Volume 171:Number 22(2014:Nov.)
• Page Start: 5139
• Page End: 5153
• Publication Date: 2014-09-05
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12831
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12831-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>The aim of this study was to determine whether [platinum (Pt)(<italic>O</italic><italic>, </italic><italic>O</italic><italic>′</italic>‐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.</p> </sec> <sec id="bph12831-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>We performed experiments on cancerous and normal epithelial breast cells in primary culture obtained from the same patients. The apoptotic effects [Pt(<italic>O</italic><italic>, </italic><italic>O</italic><italic>′</italic>‐acac)(γ‐acac)(DMS)] and cisplatin in cancerous and normal breast cells were compared.</p> </sec> <sec id="bph12831-sec-0003" sec-type="section"> <title>Key Results</title> <p>Cancer cells were more sensitive to [Pt(<italic>O</italic><italic>, </italic><italic>O</italic><italic>′</italic>‐acac)(γ‐acac)(DMS)] (IC<sub>50</sub> = 5.22 ± 1.2 μmol·L<sup>−1</sup>) than normal cells (IC<sub>50</sub> = 116.9 ± 8.8 μmol·L<sup>−1</sup>). However, the difference was less strong when cisplatin was used (IC<sub>50</sub> = 96.0 ± 6.9 and 61.9 ± 6.1 μmol·L<sup>−1</sup> for cancer and normal cells respectively). Both compounds caused reactive oxygen species (ROS) production with different mechanisms: [Pt(<italic>O</italic><italic>, </italic><italic>O</italic><italic>′</italic>‐acac)(γ‐acac)(DMS)] quickly activated NAD(P)H oxidase while cisplatin caused a slower formation of mitochondrial ROS. Cisplatin and [Pt(<italic>O</italic><italic>, </italic><italic>O</italic><italic>′</italic>‐acac)(γ‐acac)(DMS)] caused activation of caspases, proteolysis of PARP and modulation of Bcl‐2, Bax and Bid. [Pt(<italic>O</italic><italic>, </italic><italic>O</italic><italic>′</italic>‐acac)(γ‐acac)(DMS)] also caused leakage of cytochrome c from the mitochondria. Overall, these processes proceeded more quickly in cells treated with [Pt(<italic>O</italic><italic>, </italic><italic>O</italic><italic>′</italic>‐acac)(γ‐acac)(DMS)] compared with cisplatin. [Pt(<italic>O</italic><italic>, </italic><italic>O</italic><italic>′</italic>‐acac)(γ‐acac)(DMS)] effects were faster and quantitatively greater in cancer than in normal cells. [Pt(<italic>O</italic><italic>, </italic><italic>O</italic><italic>′</italic>‐acac)(γ‐acac)(DMS)] caused a fast decrease of mitochondrial membrane potential, especially in cancer cells.</p> </sec> <sec id="bph12831-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>[Pt(<italic>O</italic><italic>, </italic><italic>O</italic><italic>′</italic>‐acac)(γ‐acac)(DMS)] was specific to breast cancer cells in primary culture, and this observation makes this compound potentially more interesting than cisplatin.</p> </sec> </abstract>