Background The treatment of diffuse large B-cell lymphoma (DLBCL) is limited by the development of resistance to therapy, and there is a need to develop novel therapeutic strategies for relapsed and refractory aggressive lymphoma. Metformin is an oral agent for type 2 diabetes that has been shown to decrease cancer risk and lower mortality in other types of cancer. Methods We performed a retrospective analysis of the RPCCC database looking at patients with DLBCL treated with front-line chemotherapy. We also performed pre-clinical studies looking at the effect of metformin on cell viability, cell number, Ki67, ATP production, apoptosis, ROS production, mitochondrial membrane potential, cell cycle, effect with chemotherapeutic agents, and rituximab. Finally, we studied mouse models to see the anti-tumor effect of metformin. Results Among diabetic patients, metformin use was associated with improved progression-free survival (PFS) and overall survival (OS) compared to diabetic patients not on metformin. Our pre-clinical studies showed metformin is itself capable of anti-tumor effects and causes cell cycle arrest in the G1 phase. Metformin induces apoptosis, ROS production, and increased mitochondrial membrane permeability. Metformin exhibited additive/synergistic effects when combined with traditional chemotherapy or rituximab in vitro. In vivo, metformin in combination with rituximab showed improved survival compared with rituximab monotherapy. Conclusions Our retrospective analysis showed that metformin with front-line chemotherapy in diabetic patients resulted in improved PFS and OS. Our pre-clinical studies demonstrate metformin has potential to re-sensitize resistant lymphoma to the chemo-immunotherapy and allow us to develop a hypothesis as to its activity in DLBCL.

中文翻译：

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二甲双胍使治疗剂敏感并改善临床前和临床弥漫性大 B 细胞淋巴瘤的预后

背景 弥漫性大 B 细胞淋巴瘤 (DLBCL) 的治疗受到耐药性发展的限制，因此需要为复发性和难治性侵袭性淋巴瘤开发新的治疗策略。二甲双胍是一种 2 型糖尿病的口服药物，已被证明可以降低癌症风险并降低其他类型癌症的死亡率。方法 我们对 RPCCC 数据库进行了回顾性分析，观察了接受一线化疗治疗的 DLBCL 患者。我们还进行了临床前研究，观察二甲双胍对细胞活力、细胞数量、Ki67、ATP 产生、细胞凋亡、ROS 产生、线粒体膜电位、细胞周期、化疗药物和利妥昔单抗的影响。最后，我们研究了小鼠模型以观察二甲双胍的抗肿瘤作用。结果 在糖尿病患者中，与未服用二甲双胍的糖尿病患者相比，使用二甲双胍可提高无进展生存期 (PFS) 和总生存期 (OS)。我们的临床前研究表明，二甲双胍本身具有抗肿瘤作用并导致细胞周期停滞在 G1 期。二甲双胍诱导细胞凋亡、活性氧产生和增加线粒体膜通透性。在体外与传统化疗或利妥昔单抗联合使用时，二甲双胍表现出相加/协同作用。在体内，与利妥昔单抗单药治疗相比，二甲双胍联合利妥昔单抗显示出改善的生存率。结论 我们的回顾性分析表明，二甲双胍联合一线化疗治疗糖尿病患者可改善 PFS 和 OS。