Metabolic Markers of MG-63 Osteosarcoma Cell Line Response to Doxorubicin and Methotrexate Treatment: Comparison to Cisplatin

• Autor(a) principal: Lamego, Inês
• Data de Publicação: 2014
• Outros Autores: Duarte, Iola F., Marques, M. Paula M., Gil, Ana M.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/45043; https://doi.org/10.1021/pr500907d
• topic: Amino Acids; Antineoplastic Agents; Biomarkers, Tumor; Cell Line, Tumor; Cell Membrane; Choline; Cisplatin; Doxorubicin; Energy Metabolism; Humans; Lipid Metabolism; Magnetic Resonance Spectroscopy; Metabolic Networks and Pathways; Metabolome; Metabolomics; Methotrexate; Molecular Structure; Multivariate Analysis; Nucleotides; Osteosarcoma

A high resolution magic angle spinning NMR metabolomics study of the effects of doxorubicin (DOX), methotrexate (MTX) and cisplatin (cDDP) on MG-63 cells is presented and unveils the cellular metabolic adaptations to these drugs, often used together in clinical protocols. Although cDDP-treated cells were confirmed to undergo extensive membrane degradation accompanied by increased neutral lipids, DOX- and MTX-treated cells showed no lipids increase and different phospholipid signatures, which suggests that (i) DOX induces significant membrane degradation, decreased membrane synthesis, and apparent inhibition of de novo lipid synthesis, and (ii) MTX induces decreased membrane synthesis, while no membrane disruption or de novo lipid synthesis seem to occur. Nucleotide signatures were in apparent agreement with the different drug action mechanisms, a link having been found between UDP-GlcNAc and the active pathways of membrane degradation and energy metabolism, for cDDP and DOX, with a relation to oxidative state and DNA degradation, for cDDP. Correlation studies unveiled drug-specific antioxidative signatures, which pinpointed m- and s-inositols, taurine, glutamate/glutamine, and possibly creatine as important in glutathione metabolism. These results illustrate the ability of NMR metabolomics to measure cellular responses to different drugs, a first step toward understanding drug synergism and the definition of new biomarkers of drug efficacy.