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.
**背景/目的：** 弥漫性大B细胞淋巴瘤（DLBCL）是最常见的非霍奇金淋巴瘤类型，其特征为起源于B细胞的侵袭性、异质性肿瘤。尤其是在复发或难治性（R/R）患者中，DLBCL的治疗仍然极具挑战性。代谢重编程是恶性细胞的标志之一。我们的研究旨在通过靶向代谢脆弱性，开发改善R/R DLBCL患者临床结局的策略。 **方法：** 我们研究了两种FDA批准的抗代谢药物——二甲双胍和L-天冬酰胺酶联合应用对DLBCL细胞代谢和存活的影响。采用核磁共振（NMR）波谱评估药物组合诱导的代谢紊乱。研究其对脂质代谢、糖酵解、谷氨酰胺分解、三羧酸（TCA）循环以及抗氧化反应的影响。通过流式细胞术（FACS）分析评估细胞凋亡的诱导情况。 **结果：** 二甲双胍和L-天冬酰胺酶的组合强烈增敏DLBCL细胞发生凋亡，且不依赖于其氧化磷酸化（OxPhos）或BCR/糖酵解状态。NMR波谱显示，该组合比任一单药诱导了更广泛的代谢紊乱。它通过改变磷脂、胆固醇和脂肪酸水平来破坏脂质代谢。此外，它抵消了二甲双胍的促糖酵解效应，降低了糖酵解和谷氨酰胺分解。它还影响对细胞能量产生和氧化还原平衡至关重要的TCA循环和抗氧化反应。此外，该组合干扰了mTORC1和MAPK信号传导这两个关键的癌症生存通路。重要的是，其有益效果已在DLBCL患者中得到了原理验证。 **结论：** 二甲双胍与L-天冬酰胺酶联合应用通过靶向多条代谢途径影响DLBCL细胞存活，可能代表一种针对R/R DLBCL患者的新型治疗方法。
肿瘤(癌症)患者之家