Diabetic concentrations of metformin inhibit platelet-mediated ovarian cancer cell progression

Abstract

Clinical studies have suggested a survival benefit in ovarian cancer patients with type 2 diabetes mellitus taking metformin, however the mechanism by which diabetic concentrations of metformin could deliver this effect is still poorly understood. Platelets not only represent an important reservoir of growth factors and angiogenic regulators, they are also known to participate in the tumor microenvironment implicated in tumor growth and dissemination. Herein, we investigated if diabetic concentrations of metformin could impinge upon the previously reported observation that platelet induces an increase in the tube forming capacity of endothelial cells (angiogenesis) and upon ovarian cancer cell aggressiveness. We demonstrate that metformin inhibits the increase in angiogenesis brought about by platelets in a mechanism that did not alter endothelial cell migration. In ovarian cancer cell lines and primary cultured cancer cells isolated from the ascitic fluid of ovarian cancer patients, we assessed the effect of combinations of platelets and metformin upon angiogenesis, migration, invasion and cancer sphere formation. The enhancement of each of these parameters by platelets was abrogated by the present of metformin in the vast majority of cancer cell cultures tested. Neither metformin nor platelets altered proliferation; however, metformin inhibited the increase in phosphorylation of focal adhesion kinase induced by platelets. We present the first evidence suggesting that concentrations of metformin present in diabetic patients may reduce the actions of platelets upon both endothelial cells and cancer cell survival and dissemination.

The impact on high‐grade serous ovarian cancer of obesity and lipid metabolism‐related gene expression patterns: the underestimated driving force affecting prognosis

“…We should also consider patient characteristics, such as weight, adiposity, use of other medications ( e.g . statins, metformin), diet and life style, all conditions that influence global gene expression and biological interactions among the different cell components present in the tumour microenvironment .…”

Wise Management of Ovarian Cancer: On the Cutting Edge

“…Treatment with metformin in vitro and in vivo in murine experiments resulted in decreased angiogenesis in metastatic tissues and attenuated ovarian cancer cell adhesion [ 65 , 66 ]. It has also been demonstrated that the reduction in neovascularization following metformin treatment can be driven by blockage of the mTOR signaling pathway [ 67 , 68 ]. Furthermore, metformin targets ALDH+ EOC stem cell populations in vitro, leading to suppressed angiogenesis, proliferation, and tumor growth [ 69 ].…”

“…As a result, EOC cells are sensitized to metformin. Furthermore, metformin may re-sensitize platinum- or paclitaxel-resistant EOC cells to chemosensitive cells, either by induction of autophagy or via its anti-inflammatory properties [ 67 , 73 ].…”

Marketed drugs used for the management of hypercholesterolemia as anticancer armament

“… 1 , 2 Importantly, a growing body of evidence suggests that several pharmacologic agents could be “repositioned” or “repurposed” in the field of oncology, owing to their interference with signaling pathways which are crucial for tumorigenesis. This notion is experimentally (at the preclinical level, clinical level or even at both levels) corroborated for marketed agents currently used for the management of different pathologic entities ranging from pain, 3 gastrointestinal disorders, 4 depression, 5 hypercholesterolemia 6 and diabetes mellitus type II 7 , 8 to human immunodeficiency virus 9 , 10 and parasitic infection. 11 , 12 …”