Metformin as a new anti-cancer drug in adrenocortical carcinoma
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Giada Poli1,*, Giulia Cantini1,*, Roberta Armignacco1,*, Rossella Fucci1, Raffaella Santi2, Letizia Canu1, Gabriella Nesi2, Massimo Mannelli1, Michaela Luconi1
1Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence Italy
2Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence Italy
*These authors contributed equally to this work
Michaela Luconi, email: [email protected]
Keywords: metformin, H295R, IGF-1R, apoptosis, tumor proliferation
Received: March 24, 2016 Accepted: June 09, 2016 Published: July 06, 2016
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.
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