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Network"]}]},{"name":"PAIR-Ob\u00e9sit\u00e9","award":["ANR-18-IDEX-0001"],"award-info":[{"award-number":["ANR-18-IDEX-0001"]}]},{"name":"PAIR-Ob\u00e9sit\u00e9","award":["INCa_1873"],"award-info":[{"award-number":["INCa_1873"]}]},{"name":"PAIR-Ob\u00e9sit\u00e9","award":["ANR-21-RHUS-0017"],"award-info":[{"award-number":["ANR-21-RHUS-0017"]}]},{"name":"PAIR-Ob\u00e9sit\u00e9","award":["ANR-23-RHUS-0010"],"award-info":[{"award-number":["ANR-23-RHUS-0010"]}]},{"name":"PAIR-Ob\u00e9sit\u00e9","award":["INCa_1873"],"award-info":[{"award-number":["INCa_1873"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, characterized by aggressive and heterogeneous tumors originating from B-cells. Especially in patients with relapsed or refractory (R\/R) disease, DLBCL remains a challenging cancer to treat. Metabolic reprogramming is a hallmark of malignant cells. Our research focuses on developing strategies to enhance clinical outcomes for R\/R DLBCL patients by targeting metabolic vulnerabilities. Methods: We investigated the effects of combining metformin and L-asparaginase, two FDA-approved antimetabolic drugs, on DLBCL cell metabolism and survival. Nuclear magnetic resonance (NMR) spectroscopy was employed to assess metabolic disturbances induced by the drug combination. The impact on lipid metabolism, glycolysis, glutaminolysis, the tricarboxylic acid (TCA) cycle, and antioxidant responses was examined. Induction of apoptosis was evaluated by FACS analysis. Results: The combination of metformin and L-asparaginase strongly sensitized DLBCL cells to apoptosis, independently of their oxidative phosphorylation (OxPhos) or BCR\/glycolytic status. NMR spectroscopy revealed that this combination induces broader metabolic disturbances than either drug alone. It disrupts lipid metabolism by altering levels of phospholipids, cholesterol, and fatty acids. Additionally, it counteracts the pro-glycolytic effect of metformin, decreases glycolysis, and reduces glutaminolysis. It also affects the TCA cycle and antioxidant responses, critical for cellular energy production and redox balance. Furthermore, this combination interferes with two key cancer survival pathways, mTORC1 and MAPK signaling. Importantly, proof of principle for its beneficial effect was demonstrated in DLBCL patients. Conclusions: Combining metformin and L-asparaginase affects DLBCL cell survival by targeting multiple metabolic pathways and may represent a novel therapeutic approach for R\/R DLBCL patients.<\/jats:p>","DOI":"10.3390\/cancers17030394","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T11:50:47Z","timestamp":1737719447000},"page":"394","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Metabolic Heterogeneity in Diffuse Large B-Cell Lymphoma Cells Reveals an Innovative Antimetabolic Combination Strategy"],"prefix":"10.3390","volume":"17","author":[{"given":"Leonardo","family":"Lordello","sequence":"first","affiliation":[{"name":"NF-\u03baB, Differentiation and Cancer, Universit\u00e9 Paris Cit\u00e9, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8617-6549","authenticated-orcid":false,"given":"St\u00e9phanie","family":"Nuan-Aliman","sequence":"additional","affiliation":[{"name":"NF-\u03baB, Differentiation and Cancer, Universit\u00e9 Paris Cit\u00e9, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karoline","family":"Kielbassa-Elkadi","sequence":"additional","affiliation":[{"name":"NF-\u03baB, Differentiation and Cancer, Universit\u00e9 Paris Cit\u00e9, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4196-1812","authenticated-orcid":false,"given":"Aur\u00e9lie","family":"Montagne","sequence":"additional","affiliation":[{"name":"NF-\u03baB, Differentiation and Cancer, Universit\u00e9 Paris Cit\u00e9, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantina","family":"Kotta","sequence":"additional","affiliation":[{"name":"NF-\u03baB, Differentiation and Cancer, Universit\u00e9 Paris Cit\u00e9, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0885-613X","authenticated-orcid":false,"given":"Isabelle","family":"Martins","sequence":"additional","affiliation":[{"name":"INSERM U1138, Equipe Labellis\u00e9e Ligue Contre le Cancer, Cordeliers Research Center, Universit\u00e9 Paris Cit\u00e9, Sorbonne Universit\u00e9, 75006 Paris, France"},{"name":"Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, 94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Pinto Jurado","sequence":"additional","affiliation":[{"name":"NF-\u03baB, Differentiation and Cancer, Universit\u00e9 Paris Cit\u00e9, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5958-9732","authenticated-orcid":false,"given":"C\u00e9dric","family":"Caradeuc","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacological and Toxicological Chemistry and Biochemistry, LPTCB, Universit\u00e9 Paris Cit\u00e9, Sorbonne Paris Cit\u00e9, UMR CNRS 8601, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6685-3354","authenticated-orcid":false,"given":"Jacqueline","family":"Lehmann-Che","sequence":"additional","affiliation":[{"name":"INSERM U976, Immunologie Humaine, Pathophysiologie, Immunoth\u00e9rapie, Universit\u00e9 Paris Cit\u00e9, 75010 Paris, France"},{"name":"Service d\u2019Oncologie Mol\u00e9culaire, AP-HP, H\u00f4pital Saint-Louis, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 \u00c1ngel","family":"Mart\u00ednez-Climent","sequence":"additional","affiliation":[{"name":"Department of Hematology, Center for Applied Medical Research, University of Navarra, IDISNA, CIBERONC, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Meignin","sequence":"additional","affiliation":[{"name":"NF-\u03baB, Differentiation and Cancer, Universit\u00e9 Paris Cit\u00e9, 75006 Paris, France"},{"name":"Department of Pathology, AP-HP, H\u00f4pital Saint-Louis, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2322-339X","authenticated-orcid":false,"given":"Nicolas","family":"Giraud","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacological and Toxicological Chemistry and Biochemistry, LPTCB, Universit\u00e9 Paris Cit\u00e9, Sorbonne Paris Cit\u00e9, UMR CNRS 8601, 75006 Paris, 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