TY - JOUR
T1 - Metabolic Heterogeneity in Diffuse Large B-Cell Lymphoma Cells Reveals an Innovative Antimetabolic Combination Strategy
AU - Lordello, Leonardo
AU - Nuan-Aliman, Stéphanie
AU - Kielbassa-Elkadi, Karoline
AU - Montagne, Aurélie
AU - Kotta, Konstantina
AU - Martins, Isabelle
AU - Pinto Jurado, Eva
AU - Caradeuc, Cédric
AU - Lehmann-Che, Jacqueline
AU - Martínez-Climent, José Ángel
AU - Meignin, Véronique
AU - Giraud, Nicolas
AU - Kroemer, Guido
AU - Bertho, Gildas
AU - Thieblemont, Catherine
AU - Baud, Véronique
N1 - Publisher Copyright:
© 2025 by the authors.
PY - 2025/2/1
Y1 - 2025/2/1
N2 - 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.
AB - 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.
KW - B-cell lymphoma
KW - apoptosis
KW - cell death
KW - combination of antimetabolic drugs
KW - diffuse large B-cell lymphoma (DLBCL)
KW - metabolism
KW - oncogenic pathways
UR - http://www.scopus.com/inward/record.url?scp=85217802269&partnerID=8YFLogxK
U2 - 10.3390/cancers17030394
DO - 10.3390/cancers17030394
M3 - Article
AN - SCOPUS:85217802269
SN - 2072-6694
VL - 17
JO - Cancers
JF - Cancers
IS - 3
M1 - 394
ER -