1H-NMR metabolomic study of SKOV-3 cells, response to the [Pt(O,O′-acac)(γ-acac)(DMS)] treatment

NMR-based metabolomic analysis of cells, tissues and biological fluids represents a helpful technique to assess drugs’ tumour response and to explore the mechanism of action and resistance of drugs. The novel Pt(II) complex, [Pt(O,O′-acac)(γ-acac)(DMS)], Ptac2S, has recently gained increasing attention as potential anticancer agent for its pharmacological activity shown in different in vitro cultured tumoral cell lines, and in vivo. In this work, an 1H NMR metabolomic approach was used to evaluate the pharmacological activity of on Epithelial Ovarian Carcinoma (EOC) cisplatin resistant cultured cell line (i.e. SKOV-3 cell line). The multivariate spectroscopic NMR data of both intracellular cell extracts (aqueous and lipidic fractions) and extracellular medium, recover of Ptac2S treated cells, as made by using chemo-metric and pattern recognition techniques. These metabolic profiles were compared to those of untreated and cisplatin treated (at the IC50 dose) SKOV-3 cells, following the same cells for a range of culture times (6-24 h) to evidence variations. The multivariate data analysis revealed the ability of the considered complex to act already 6h after treatment. In particular, it was observed a fast decreasing of succinate (a Krebs’ cycle intermediate) and phosphocholine (an intermediate in the synthesis of phosphatidylcholine, a major component of biological membranes), with respect to untreated and cisplatin treated cells. Similar effects were observed in cisplatin treated cell samples only 24h after treatment. Furthermore, Ptac2S samples showed a decrease of the relative content of cholesterol, triglycerides and polyunsaturated fatty acids. On the contrary, controls and cisplatin treated cells showed an increase of these latter metabolites, which is often associated to proliferation and/or apoptosis phenomena. Finally, the analysis of recovered culture media revealed a preferential release of pyruvate from Ptac2S treated cells, with respect to the cisplatin treated and control cells, characterized by a higher release of lactate. This suggests a possible inhibition of both pyruvate entrance, in the Krebs cycle, and/or pyruvate conversion into lactate. Last condition seems typical of cancer cells (Warburg Effect). In conclusion, these results confirm that Ptac2S limits the proliferation of cancerous cells with a mechanism very different from that of cisplatin.