Investigating the antitumor effects of a novel ruthenium (II) complex on malignant melanoma cells: An NMR-based metabolomic approach.

Metals have been used for many years in medicine, particularly for the treatment of cancer. Cisplatin is one of the most used drugs in the treatment of cancer. Although platinum-containing therapeutics have unparalleled efficacy in cancer treatment, they are coupled with adverse effects and the development of tumour resistance. This has led to the exploration of other metal-based modalities including ruthenium-based compounds. Thus, in our previous study, we synthesized and characterized a novel ruthenium (II) complex (referred to herein as GA113) containing a bis-amino-phosphine ligand. The complex was subsequently screened for its anti-cancerous potential against a human malignant melanoma A375 cell line and findings revealed favourable cytotoxicity. In the current study, a nuclear magnetic resonance (NMR)-based cellular metabolomics approach was applied to probe the possible mechanism of GA113 in A375 cells. In addition, other biological assays including light microscopy, Hoechst-33258 and MitoTracker Orange CM-H2TMRos stain were used to assess cellular viability and apoptosis in GA113-treated cells. Consequently, multivariate statistical data analysis was applied to the metabolomic data to identify potential biomarkers. Six signatory metabolites were altered after treatment. Changes in these metabolites were linked to two metabolic pathways, which include the alanine, aspartate, and glutamate metabolic pathway as well as the glycine, serine, and threonine pathway. By means of an NMR-based metabolomic approach, we identified the potential mechanism of action of complex GA113 in A375 cancer cells thus providing new insights into the metabolic pathways affected by complex GA113 and establishing a foundation for further development, research, and eventual application in cancer.

Synthesis and anti-cancer activity of bis-amino-phosphine ligand and its ruthenium(II) complexes.

The development of both chemotherapeutic drug resistance as well as adverse side effects suggest that the current chemotherapeutic drugs remain ineffective in treating the various types of cancers. The development of new metallodrugs presenting anti-cancer activity is therefore needed. Ruthenium complexes have gained a great deal of interest due to their promising anti-tumour properties and reduced toxicity in vivo. This study highlighted the effective induction of cell death in a malignant melanoma cell by two novel bis-amino-phosphine ruthenium(II) complexes referred to as GA105 and GA113. The IC50 concentrations were determined for both the complexes, the ligand and cisplatin, for comparison. Both complexes GA105 and GA113 displayed a high anti-cancer selectivity profile as they exhibited low IC50 values of 6.72 µM and 8.76 µM respectively, with low toxicity towards a non-malignant human cell line. The IC50 values obtained for both complexes were lower than that of cisplatin. The new complexes were more effective compared to the free ligand, GA103 (IC50 = >20 µM). Morphological studies on treated cells induced apoptotic features, which with further studies could indicate an intrinsic cell death pathway. Additionally, flow cytometric analysis revealed that the mode of cell death of complex GA113 was apoptosis. The outcomes herein give further insight into the potential use of selected Ru(II) complexes as alternative chemotherapeutic drugs in the future.