title: 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.
authors.affiliation: Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Poli
authors.affiliation: Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Cantini
authors.affiliation: Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Armignacco
authors.affiliation: Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Fucci
authors.affiliation: Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Santi
authors.affiliation: Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Canu
authors.affiliation: Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Nesi
authors.affiliation: Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mannelli
authors.affiliation: Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Michaela
authors.initials: M
authors.lastname: Luconi
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy / Q000473:pathology*; D018268:Adrenocortical Carcinoma / Q000188:drug therapy / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D005947:Glucose / Q000737:chemistry; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015995:Prevalence
chemical_list: D000970:Antineoplastic Agents; D008687:Metformin; C505407:CASP3 protein, human; D053148:Caspase 3; D005947:Glucose
keywords: H295R; IGF-1R; apoptosis; metformin; tumor proliferation