title: Investigating a signature of temozolomide resistance in GBM cell lines using metabolomics.
abstract: Glioblastoma multiforme (GBM) is the most common form of malignant glioma. Current therapeutic approach to treat this malignancy involves a combination of surgery, radiotherapy and chemotherapy with temozolomide. Numerous mechanisms contributing to inherent and acquired resistance to this chemotherapeutic agent have been identified and can lead to treatment failure. This study undertook a metabolomics-based approach to characterize the metabolic profiles observed in temozolomide-sensitive and temozolomide-resistant GBM cell lines as well as in a small sub-set of primary GBM tumors. This approach was also utilized to explore the metabolic changes modulated upon cell treatment with temozolomide and lomeguatrib, an MGMT inhibitor with temozolomide-sensitizing potential. Metabolites previously explored for their potential role in chemoresistance including glucose, citrate and isocitrate demonstrated elevated levels in temozolomide-resistant GBM cells. In addition, a signature of metabolites comprising alanine, choline, creatine and phosphorylcholine was identified as up-regulated in sensitive GBM cell line across different treatments. These results present the metabolic profiles associated with temozolomide response in selected GBM models and propose interesting leads that could be leveraged for the development of therapeutic or diagnostic tools to impact temozolomide response in GBMs.
authors: Department of Chemistry and Biochemistry, Université de Moncton, 18 Antonine-Maillet Avenue, Moncton, NB, E1A 3E9, Canada.
authors: Patrick-Denis
authors: PD
authors: St-Coeur
authors: Department of Chemistry and Biochemistry, Université de Moncton, 18 Antonine-Maillet Avenue, Moncton, NB, E1A 3E9, Canada.
authors: Julie J
authors: JJ
authors: Poitras
authors: National Research Council of Canada, 100 des Aboiteaux Street, Moncton, NB, E1A 7R1, Canada.
authors: Miroslava
authors: M
authors: Cuperlovic-Culf
authors: Department of Chemistry and Biochemistry, Université de Moncton, 18 Antonine-Maillet Avenue, Moncton, NB, E1A 3E9, Canada.
authors: Mohamed
authors: M
authors: Touaibia
authors: Department of Chemistry and Biochemistry, Université de Moncton, 18 Antonine-Maillet Avenue, Moncton, NB, E1A 3E9, Canada. pier.morin@umoncton.ca.
authors: Pier
authors: P
authors: Morin
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015180:Electrophoresis, Gel, Two-Dimensional; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D055432:Metabolomics; D011687:Purines / Q000494:pharmacology; D000077204:Temozolomide; D014316:Tritium / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D011687:Purines; D025521:Tumor Suppressor Proteins; D014316:Tritium; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; C521206:lomeguatrib; D000077204:Temozolomide
keywords: Cancer diagnosis; Cancer therapeutics; Glioblastoma multiforme; Lomeguatrib; Metabolomics; Temozolomide