Strong antineoplastic effects of metformin in preclinical models of liver carcinogenesis.
Studies suggest that metformin, widely used for treating Type 2 diabetes, possesses innate antineoplastic properties. For metabolic syndrome patients with hepatocellular carcinoma (HCC), metformin may provide antitumoral effects. We evaluated the impact of metformin on tumour growth and visceral fat composition using relevant preclinical models of metabolic syndrome. Studies were performed in three hepatoma cell lines, in HepG2 xenograft mice fed with standard chow (SC) diet, 60% high-fat diet (HFD) or 30% fructose diet (FR), and an ex vivo model of human cultured HCC slices. Visceral fatty acid composition was analysed by magnetic resonance imaging (MRI). Metformin had a dose-dependent inhibitory effect on cell proliferation and apoptosis in vitro through the deregulation of mTOR/AMPK, AKT and extracellular signal regulated kinase (ERK) signalling pathways. Tumour engraftment rates were higher in HFD mice than SC mice (hepatic: 79% compared with 25%, P=0.02) and FR mice (subcutaneous: 86% compared with 50%, P=0.04). Subcutaneous tumour volume was increased in HFD mice (+64% compared with FR and SC, P=0.03). Metformin significantly decreased subcutaneous tumour growth via cell-cycle block and mammalian target of rapamycin (mTOR) pathway inhibition, and also induced hypoxia and decreased angiogenesis. In ex vivo tumour slices, metformin treatment led to increased necrosis, decreased cyclin D1 and increased carbonic anhydrase-9 (CA-9). Metformin caused qualitative changes in visceral fat composition of HFD mice, with decreased proportions of polyunsaturated fatty acids (14.6% ± 2.3% compared with 17.9% ± 3.0%, P=0.04). The potent antitumoral effects of metformin in multiple preclinical models implicating several molecular mechanisms provide a strong rationale for clinical trials including combination studies in HCC patients.
INSERM UMR 1149, Inflammation Research Center, Paris-Diderot University, Paris, France.|Hepatobiliary Surgery and Liver Transplantation Department, Beaujon Hospital, APHP, Clichy 92110, France.
François
F
Cauchy
INSERM UMR 1149, Inflammation Research Center, Paris-Diderot University, Paris, France.
Mouniya
M
Mebarki
INSERM UMR 1149, Inflammation Research Center, Paris-Diderot University, Paris, France.
Benjamin
B
Leporq
INSERM UMR 1149, Inflammation Research Center, Paris-Diderot University, Paris, France.
Samira
S
Laouirem
Pathology Department, Beaujon Hospital, APHP, Clichy 92110, France.
Miguel
M
Albuquerque
INSERM UMR 1149, Inflammation Research Center, Paris-Diderot University, Paris, France.
Simon
S
Lambert
Pathology Department, Beaujon Hospital, APHP, Clichy 92110, France.
Pierre
P
Bourgoin
Hepatobiliary Surgery and Liver Transplantation Department, Beaujon Hospital, APHP, Clichy 92110, France.
Olivier
O
Soubrane
INSERM UMR 1149, Inflammation Research Center, Paris-Diderot University, Paris, France.|Radiology Department, Beaujon Hospital, APHP, Clichy 92110, France.
Bernard E
BE
Van Beers
INSERM UMR 1149, Inflammation Research Center, Paris-Diderot University, Paris, France.
Sandrine
S
Faivre
INSERM UMR 1149, Inflammation Research Center, Paris-Diderot University, Paris, France.|Pathology Department, Beaujon Hospital, APHP, Clichy 92110, France.
Pierre
P
Bedossa
INSERM UMR 1149, Inflammation Research Center, Paris-Diderot University, Paris, France vparadis@teaser.fr.|Pathology Department, Beaujon Hospital, APHP, Clichy 92110, France.
Valérie
V
Paradis
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D000071231:Carbonic Anhydrase IX / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D019938:Cyclin D1; D008687:Metformin; D000071231:Carbonic Anhydrase IX
hepatocellular carcinoma; hypoxia; magnetic resonance imaging (MRI); metabolic syndrome; metformin