Metformin prevents nerve growth factor-dependent proliferative and proangiogenic effects in epithelial ovarian cancer cells and endothelial cells

Abstract

Background:Epithelial ovarian cancer (EOC) is characterized by exacerbated angiogenesis regulated by proangiogenic and growth factors. Nerve growth factor (NGF) is overexpressed in EOC where it promotes proliferation as well as survival and is considered a proangiogenic factor. Metformin, a drug commonly used in the treatment of diabetes, is attributed to antineoplastic effects, but the underlying mechanisms remain unknown. Given that current therapies yield modest results in EOC patients, the aim of this study was to determine the effects of metformin on NGF-enhanced proliferation of EOC cells and the angiogenic potential of endothelial cells.Methods:A2780 (EOC), HOSE (human ovarian surface epithelial) and EA.hy926 (endothelial) cells were treated with NGF and metformin. Cell viability, cell proliferation and cell cycle were evaluated in all three cell lines, and the angiogenic potential in endothelial EA.hy926 cells.Results:NGF enhanced cell proliferation in A2780, HOSE and EA.hy926 cells (p < 0.05), while metformin treatment decreased cell proliferation in A2780 and EA.hy926 cells (p < 0.05). Moreover, the NGF-enhanced angiogenic score in EA.hy926 cells was prevented by metformin (p < 0.05).Conclusions:Given that NGF plays a significant role in EOC progression, our current findings suggest that metformin holds considerable promise as an adjuvant treatment in ovarian cancer.

Antitumoral Effects of Metformin in Ovarian Cancer

“…In agreement with the metformin-depending decrease of c-MYC in ovarian cancer cells, metformin induces the degradation of cyclin D1 [33,38], a protein required for progression from G1 to S phase of the cell cycle, and increases p21 expression (a negative regulator of cell cycle) [67]. These results are consistent with experiments performed in primary ovarian cancer cell cultures and ovarian cancer cell lines, which show that metformin induces cell cycle arrest in the G0/G1 phase and decreases the percentage of cells in S phase of the cellular cycle [35,68,69]. These findings highly suggest that metformin decreases the progression of the cell cycle in ovarian cancer cells.…”

“…On the other hand, metformin treatment (in millimolar concentrations) displays direct effects in the endothelial cells, by reducing cell proliferation in human umbilical vein endothelial cells (HUVEC) and endothelial progenitor cells [89,90]. Similar results were replicated by our group where metformin decreases cell proliferation of the endothelial cell line EA.hy926, in a dose-dependent manner [35], as well as, the endothelial cell differentiation (Figure 1). These results suggest that metformin affects in a direct manner the angiogenesis potential of endothelial cells.…”

“…Several studies have shown that metformin displays direct antitumoral effects. Most of these studies have been performed in ovarian cancer cell lines, where metformin impairs cell proliferation, migration, and angiogenesis potential and enhances the chemotherapy sensibility [33][34][35][36].…”

“…These signaling pathways are associated with an increase of cell proliferation in most kinds of cancer cells [50,51]. Some studies have shown that metformin treatment decreases IGF-1 and insulin levels, in a mice model with ovarian cancer [51], and also metformin treatment blocks the pro-tumoral effects of the nerve growth factor (NGF) in epithelial ovarian cancer cells [35] or the insulin/IGF-I signaling in uterine serous carcinoma [52].…”

<p>Correlation of NRF2 and progesterone receptor and its effects on ovarian cancer biology</p>

“…45,49,50 Interestingly, recent studies show that metformin, usually applied in diabetic patients, prevents tumor growth, induces apoptosis and increases sensitivity to chemotherapy in ovarian cancer cells. [51][52][53][54][55][56][57] Mechanisms underlying these cellular effects include suppression of cancer stem cells, inhibition of epithelial-to-mesenchymal transition and interference with neoplastic cell metabolism. [58][59][60][61][62] Following promising data of epidemiological studies showing a favorable effect of metformin on ovarian cancer Figure 6 Summary of the hypothesized interaction within the NRF2/AKR1C1/PR pathway.…”