Metabolic markers of MG-63 osteosarcoma cell line response to doxorubicin and methotrexate treatment: comparison to cisplatin.
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.
CICECO-Departmento de Química, Universidade de Aveiro , Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.
Inês
I
Lamego
Iola F
IF
Duarte
M Paula M
MP
Marques
Ana M
AM
Gil
D000596:Amino Acids / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055442:Metabolome / Q000187:drug effects*; D055432:Metabolomics / Q000379:methods*; D008727:Methotrexate / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D015999:Multivariate Analysis; D009711:Nucleotides / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology
D000596:Amino Acids; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009711:Nucleotides; D004317:Doxorubicin; D002794:Choline; D002945:Cisplatin; D008727:Methotrexate
MG-63 cell line; NMR spectroscopy; cancer; chemotherapy; cisplatin; doxorubicin; metabolomics; methotrexate; osteosarcoma