Metformin, an anti-diabetic drug commonly used for type 2 diabetes therapy, is associated with a decreased risk for certain cancer. Due to extensive reports of its in vitro and in vivo anti-tumor activity, we and others have focused on the anti-angiogenic potential as a possible mechanism through which metformin could affect tumor progression, and to propose its use as an angiopreventive drug. Metformin was able to interfere with endothelial cell proliferation, apoptosis and invasion in vitro. Gene arrays analyses were performed to verify the effect of metformin on endothelial gene expression profiles and the matrigel sponge assay to test its effect in vivo.
We show that metformin inhibited endothelial cell proliferation by effecting cell cycle regulation rather than inducing apoptosis. In vitro, metformin reduces endothelial cell invasion and represses their ability to organize into capillary-like networks. These effects are partially reverted by compound C, a specific inhibitor of AMPK, confirming that metformin could interfere with angiogenesis responses by activating AMPK signaling. Gene expression profiles of endothelial cells treated with metformin showed down-regulation of several angiogenesis-related genes but up-regulation of chemokine pathways. In vivo, metformin inhibited angiogenesis induced by VEGF. Considering the strict correlation between type II diabetes and obesity, we evaluated the ability of Metformin to modulate endothelial precursor cells in an obese murine model and we reported that Metformin decreases the number of adipose tissue progenitor endothelial cells in vivo only in obese mice.
These data suggest that metformin has anti-angiogenic effect associated with down-regulation of specific molecule although it also induces some inflammatory mediators, and that it may be most effective in the context of obesity.
Citation Format: Katiuscia Dallaglio, Antonino Bruno, Anna Rita Cantelmo, Ulrich Pfeffer, Francesco Bertolini, Douglas M. Noonan, Adriana Albini. Metformin as a potent antiangiogenic factor: From diabetes to cancer angioprevention. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A23.