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Metformin sensitizes therapeutic agents and improves outcome in pre-clinical and clinical diffuse large B-cell
Anil R Singh1, Juan J Gu2,3, Qunling Zhang4
1Texas Oncology, Texas, USA.
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.
Insights
Metformin may improve survival in diffuse large B-cell lymphoma (DLBCL) patients. This study found metformin improved progression-free survival and overall survival in diabetic DLBCL patients and showed anti-tumor effects in pre-clinical models.
Area of Science:
- Oncology
- Pharmacology
- Hematology
Background:
- Diffuse large B-cell lymphoma (DLBCL) treatment is challenged by therapy resistance.
- Novel strategies are needed for relapsed and refractory aggressive lymphoma.
- Metformin, a diabetes drug, shows potential anti-cancer properties.
Purpose of the Study:
- To investigate the efficacy of metformin in DLBCL treatment.
- To evaluate metformin's effects on lymphoma cells and in pre-clinical models.
- To explore metformin's potential to overcome therapeutic resistance.
Main Methods:
- Retrospective analysis of DLBCL patients treated with front-line chemotherapy.
- Pre-clinical studies assessing metformin's impact on cell viability, apoptosis, cell cycle, and mitochondrial function.
- In vivo studies using mouse models to evaluate metformin's anti-tumor effects, alone and in combination with rituximab.
Main Results:
- Metformin use in diabetic DLBCL patients correlated with improved progression-free survival (PFS) and overall survival (OS).
- Pre-clinical studies revealed metformin's intrinsic anti-tumor activity, inducing G1 cell cycle arrest, apoptosis, and ROS production.
- Metformin demonstrated additive/synergistic effects with chemotherapy and rituximab in vitro, and improved survival with rituximab in vivo.
Conclusions:
- Metformin combined with front-line chemotherapy improved PFS and OS in diabetic DLBCL patients.
- Pre-clinical data suggest metformin can re-sensitize resistant lymphoma to chemo-immunotherapy.
- Metformin shows promise as a therapeutic agent for DLBCL.
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