Metabolic reprogramming in malignant A375 cells treated with a ruthenium (II) complex: insights from GCxGC-TOF/MS metabolomics.

Abstract

Introduction: Melanoma is an aggressive form of cancer characterised by its high metabolic adaptability that contributes to drug resistance. To this end, ruthenium complexes have emerged as a promising class of compounds in the discovery of cancer drugs due to their unique chemical properties and potential to overcome some of the limitations of conventional chemotherapy. In our previous study, we synthesised, characterised, and performed cytotoxicity tests of a ruthenium (II) complex (GA113) against the malignant A375 melanoma cell line. Our previous findings revealed favourable cytotoxicity, with an IC₅₀ value of 8.76 µM which formed the basis current study.

Objective: Elucidate the metabolic mechanism of GA113 in malignant A753 melanoma cells.

Method: A two-dimensional gas chromatography time-of-flight mass spectrometry (GCxGC-TOF/MS) cellular metabolomics approach was used, and univariate and multivariate statistical methods were applied to the metabolomics data.

Results: 33 metabolites were identified as significant discriminators between GA113-treated and untreated A375 melanoma cells. Changes in 19 of these 33 metabolites were mapped to pantothenate and coenzyme A biosynthesis, citrate cycle, cysteine and methionine metabolism, arginine and proline metabolism, and alanine, aspartate, and glutamate metabolism.

Conclusion: These findings suggest that GA113 exerts its anticancer effects by disrupting essential metabolic pathways in melanoma cells, which presents a promising therapeutic avenue to target melanoma metabolism.