Metformin exerts antitumor activity via induction of multiple death pathways in tumor cells and activation of a protective immune response

Abstract

The antitumor effect of metformin has been demonstrated in several types of cancer; however, the mechanisms involved are incompletely understood. In this study, we showed that metformin acts directly on melanoma cells as well as on the tumor microenvironment, particularly in the context of the immune response. In vitro, metformin induces a complex interplay between apoptosis and autophagy in melanoma cells. The anti-metastatic activity of metformin in vivo was assessed in several mouse models challenged with B16F10 cells. Metformin's activity was, in part, immune system-dependent, whereas its antitumor properties were abrogated in immunodeficient (NSG) mice. Metformin treatment increased the number of lung CD8-effector-memory T and CD4+Foxp3+IL-10+ T cells in B16F10-transplanted mice. It also decreased the levels of Gr-1+CD11b+ and RORγ+ IL17+CD4+ cells in B16F10-injected mice and the anti-metastatic effect was impaired in RAG-1−/− mice challenged with B16F10 cells, suggesting an important role for T cells in the protection induced by metformin. Finally, metformin in combination with the clinical metabolic agents rapamycin and sitagliptin showed a higher antitumor effect. The metformin/sitagliptin combination was effective in a BRAFV600E/PTEN tamoxifen-inducible murine melanoma model. Taken together, these results suggest that metformin has a pronounced effect on melanoma cells, including the induction of a strong protective immune response in the tumor microenvironment, leading to tumor growth control, and the combination with other metabolic agents may increase this effect.

Dipeptidyl peptidase 4 inhibitors as novel agents in improving survival in diabetic patients with colorectal cancer and lung cancer: A Surveillance Epidemiology and Endpoint Research Medicare study

“…Although there is no direct comparison, the comparative improvement of HR for a combination of DPP4 inhibitors and metformin as compared to either drug alone is encouraging and suggests an additive effect on OS of the combination. This finding was also noticed in the in-vivo study by Pereira et al 10 Our study is based on SEER-Medicare data until 2013 prior to the use of immunotherapy drugs for cancer treatment. It will be interesting to see how DPP4 inhibitors interplay with immunotherapy drugs as suggested by Barreira da Silva et al 9 As we mentioned before, various preclinical or in-vivo studies have shown the role of DPP4/CD26 in either suppressing or activating tumor cells.…”

“…Similarly, Pereira et al showed that in mice models with melanoma, treatment with metformin or sitagliptin showed a significant reduction in the number of metastatic lung nodules. Importantly, the combination of metformin with sitagliptin showed a greater reduction in the number of metastatic lung nodules than treatment with metformin or sitagliptin alone . In the mouse xenograft model with papillary thyroid cancer, sitagliptin use was associated with reduced tumor growth, with the transforming growth factor‐β signaling pathway being potentially involved .…”

“…Importantly, the combination of metformin with sitagliptin showed a greater reduction in the number of metastatic lung nodules than treatment with metformin or sitagliptin alone. 10 In the mouse xenograft model with papillary thyroid cancer, sitagliptin use was associated with reduced tumor growth, with the transforming growth factor-β signaling pathway being potentially involved. 5 In contradiction to these findings, Wang et al 11 demonstrated in an in-vivo study that use of DPP4 inhibitors increased the risk of metastasis in colon, hepatic, lung, ovary, and melanoma cell lines.…”

Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

“…So far, the contribution of AMPK-induced changes in cellular metabolism to the antiinflammatory effects of metformin remains unknown and deserves dedicated investigation. Moreover, since the immunomodulatory properties of metformin have also been proposed to underlie some of its beneficial effects on auto-immune inflammatory diseases [131][132][133][134] and cancer [135][136][137][138] , further studies are required to decipher the immune-mediated mode of action of metformin.…”

Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy

“…37,38 The ability of metformin to promote anti-tumor effects by rescuing exhausted CD8 + TILs in the TME of highly immunogenic tumors, including leukemia, melanoma, renal cell carcinoma, non-small-cell lung carcinoma, intestinal carcinoma, and breast cancer, 37 has been confirmed and extended by the observation that it significantly augments the ability of CD8 + effector memory T-cells to mediate anti-metastatic activity in melanoma models. 39 Such a promotion of a strong cancerprotective immune response was accompanied by the additional induction of local and systemic cytokine responses including production of IL-10 by metformin-expanded CD4 + regulatory T-cells, a key mechanism to enhance effector and memory CD8 + T-cell functions. 40,41 The supra-additive capacity of metformin to prevent melanoma metastases to the lung when used with other clinically relevant anti-metabolic drugs, such as rapamycin and the dipeptidyl peptidase 4 inhibitor sitagliptin, 39 further bolsters the clinical value of metformin against different facets of T-cell immunometabolism.…”