Metformin as a new anti-cancer drug in adrenocortical carcinoma

Abstract

Adrenocortical carcinoma (ACC) is a rare heterogeneous malignancy with poor prognosis. Since radical surgery is the only available treatment, more specific and effective drugs are urgently required. The anti-diabetic drug metformin has been associated with a decreased cancer prevalence and mortality in several solid tumors, prompting its possible use for ACC treatment.This paper evaluates the in vitro and in vivo anti-cancer effects of metformin using the ACC cell model H295R.Metformin treatment significantly reduces cell viability and proliferation in a dose- and time-dependent manner and associates with a significant inhibition of ERK1/2 and mTOR phosphorylation/activation, as well as with stimulation of AMPK activity. Metformin also triggers the apoptotic pathway, shown by the decreased expression of Bcl-2 and HSP27, HSP60 and HSP70, and enhanced membrane exposure of annexin V, resulting in activation of caspase-3 apoptotic effector. Metformin interferes with the proliferative autocrine loop of IGF2/IGF-1R, which supports adrenal cancer growth. Finally, in the ACC xenograft mouse model, obtained by subcutaneous injection of H295R cells, metformin intraperitoneal administration inhibits tumor growth, confirmed by the significant reduction of Ki67%.Our data suggest that metformin inhibits H295R cell growth both in vitro and in vivo. Further preclinical studies are necessary to validate the potential anti-cancer effect of metformin in patients affected by ACC.

Metformin inhibits gastric cancer cells metastatic traits through suppression of epithelial-mesenchymal transition in a glucose-independent manner

“…Metformin inhibits EMT at the range of 2.5–50 mM in different cell lines [6, 17, 18, 25, 26]. We used 10 mM metformin in our study, which is around 200-fold higher than the plasma level of metformin in type 2 diabetic patients [27].…”

Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor Regression In Vivo

“…Numerous preclinical in vivo (4,6,12,27,28) and in vitro (5,7-9,14,29) cancer models have provided evidence of metformin's anti-tumorigenic potential, which is commonly attributed to indirect whole-body effects (insulin-dependent) and/or direct (insulin-independent) effects (30). Metformin has been shown to reduce hyperinsulinemia and glycemia thereby reducing tumor cell insulin receptor (IR) expression and downstream signaling (30).…”

Chloride intracellular channel 1 regulates the antineoplastic effects of metformin in gallbladder cancer cells

“…Even though metformin has been used mainly as a first‐line drug for the treatment of type 2 diabetes, the results from a number of large‐scale epidemiologic and laboratory studies suggest that metformin may also exert anticancer effects through a different mechanism . Due to the rarity of gallbladder carcinoma, no data are currently available regarding cancer prevalence and metformin treatment in patients with GBC, nor is there evidence on the concrete effects of metformin on tumor growth.…”

“…Even though metformin has been used mainly as a first-line drug for the treatment of type 2 diabetes, the results from a number of large-scale epidemiologic and laboratory studies suggest that metformin may also exert anticancer effects through a different mechanism. (23) Due to the rarity of gallbladder carcinoma, no data are currently available regarding cancer prevalence and metformin treatment in patients with GBC, nor is there evidence on the concrete effects of metformin on tumor growth. In this study, we not only demonstrated that metformin is capable of inhibiting gallbladder cancer cell viability and inducing apoptosis by inhibiting the PI3K-Akt axis and the Bcl2 family but also revealed the regulatory roles of chloride intracellular channel 1 (CLIC1) in the resistance of GBC to metformin.…”