Singh Anil R, Gu Juan J, Zhang Qunling, Torka Pallawi, Sundaram Suchitra, Mavis Cory, Hernandez-Ilizaliturri Francisco J
Texas Oncology, Texas, USA.
Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, USA.
Cancer Metab. 2020 Jul 6;8:10. doi: 10.1186/s40170-020-00213-w. eCollection 2020.
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.
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.
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.
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.
弥漫性大B细胞淋巴瘤（DLBCL）的治疗因对治疗产生耐药性而受到限制，因此需要为复发和难治性侵袭性淋巴瘤开发新的治疗策略。二甲双胍是一种用于治疗2型糖尿病的口服药物，已被证明可降低癌症风险并降低其他类型癌症的死亡率。
我们对RPCCC数据库进行了回顾性分析，观察接受一线化疗的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生成、细胞凋亡、活性氧生成、线粒体膜电位、细胞周期、与化疗药物及利妥昔单抗联合使用的效果。最后，我们研究了小鼠模型以观察二甲双胍的抗肿瘤作用。
在糖尿病患者中，与未使用二甲双胍的糖尿病患者相比，使用二甲双胍与无进展生存期（PFS）和总生存期（OS）的改善相关。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、活性氧生成并增加线粒体膜通透性。在体外，二甲双胍与传统化疗或利妥昔单抗联合使用时表现出相加/协同作用。在体内，二甲双胍与利妥昔单抗联合使用与利妥昔单抗单药治疗相比生存期得到改善。
我们的回顾性分析表明，糖尿病患者在一线化疗中使用二甲双胍可改善PFS和OS。我们的临床前研究表明，二甲双胍有可能使耐药淋巴瘤对化疗免疫疗法重新敏感，并使我们能够就其在DLBCL中的活性提出一个假设。
