Metformin as a new anti-cancer drug in adrenocortical carcinoma.

Giada Poli,Giulia Cantini,Roberta Armignacco,Rossella Fucci,Massimo Mannelli,Raffaella Santi,Michaela Luconi,Gabriella Nesi,Letizia Canu

doi:10.18632/oncotarget.10421

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.

Highlights

Despite its rarity (1:2 million prevalence), adrenocortical cancer (ACC) deserves more consideration on account of its aggressive behavior and poor prognosis when metastatic at diagnosis
In vitro administration of increasing doses of metformin resulted in a dose- and time-dependent decrease of cell viability, which was statistically significant starting from 24 hours, as assessed by MTS assay in both the H295R (Figure 1A) and SW13 (Figure 1B) cell lines
Once shown that metformin significantly affected viability of both cell lines, we chose to focus on the effects in H295R, since this cell model better represents the secreting form of Adrenocortical carcinoma (ACC)

Summary

Introduction

Despite its rarity (1:2 million prevalence), adrenocortical cancer (ACC) deserves more consideration on account of its aggressive behavior and poor prognosis when metastatic at diagnosis. The mechanism by which mitotane acts on cancer cells, as well as on the normal adrenal, is still far from being fully elucidated. In such a scenario, it is mandatory to combine mitotane with other drugs, in order to improve the therapeutic efficacy and reduce treatment toxicity. Epidemiological studies and meta-analyses on large cohorts of diabetic patients have demonstrated a significant association between metformin and a reduced incidence www.impactjournals.com/oncotarget of various types of solid tumors [4,5,6,7], supporting the potential use of metformin as an anti-cancer drug [8]. A considerable number of studies have demonstrated the anti-cancer activity of this drug both in in vitro and in vivo tumor models, highlighting a direct anti-proliferative and pro-apoptotic effect on cancer cells and an indirect action on metabolic regulation [8, 9]

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