Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 mice

Tajima, Kazuki; Nakamura, Akinobu; Shirakawa, Jun; Togashi, Yuichi; Orime, Kazuki; Sato, Koichiro; Inoue, Hideaki; Kaji, Mitsuyo; Sakamoto, Eri; Ito, Yuzuru; Aoki, Kaztaka; Nagashima, Yoji; Atsumi, Tatsuya; Terauchi, Yasuo

doi:10.1152/ajpendo.00133.2013

Cited by 52 publications

(58 citation statements)

References 46 publications

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“…Of note, Tajima et al found that metformin decreased HCC incidence when administered concurrently with high fat diet for 60 weeks; however, metformin failed to protect against liver tumorigenesis if treatment was delayed until week 30. 33 While the efficacy of metformin is probably dependent upon both the amount of underlying disease present at the time of treatment in addition to the duration of treatment, our study definitely provides further evidence that early and long-term treatment with metformin is a promising strategy in the prevention of tumors within the liver, its main site of action. 34 …”

Section: Discussionmentioning

confidence: 61%

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Metformin prevents hepatocellular carcinoma development by suppressing hepatic progenitor cell activation in a rat model of cirrhosis

DePeralta

Wei

Ghoshal

et al. 2016

Cancer

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Background Hepatocellular carcinoma (HCC) associated mortality is increasing at an alarming rate and there is a readily identifiable cohort of at risk patients with cirrhosis, viral hepatitis, non-alcoholic fatty liver disease, and diabetes. These patients are candidates for chemoprevention. Metformin is an attractive agent for chemoprevention since it is inexpensive, has a favorable safety profile and is well tolerated over long time periods. Methods We studied the efficacy of metformin as a prevention agent in a clinically relevant rat model of HCC, where tumors develop in the setting of chronic inflammation and cirrhosis. We used repeated injections of diethylnitrosamine to induce sequential cirrhosis and HCC and administered metformin either at the first signs of fibrosis or cirrhosis. Results Prolonged metformin exposure was safe and associated with decreases in fibrotic and inflammatory markers especially when administered early at the first signs of fibrosis. In addition, early metformin treatment led to a 44% decrease in HCC incidence, while tumor burden was unchanged when metformin was administered at the first signs of cirrhosis. Interestingly, activation of the hepatic progenitor/stem cell compartment was first observed at the onset of cirrhosis and therefore only early metformin treatment suppressed receptor for advanced glycation end products and inhibited the activation of hepatic progenitor cells. Conclusions Our results are the first to demonstrate an effect on progenitor/stem cells in the setting of chemoprevention and provide further rationale to explore metformin as an early intervention in clinical trials of patients with chronic liver disease at high risk for HCC.

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Section: Discussionmentioning

confidence: 61%

“…Interestingly, metformin also did not change levels of lipogenioc genes, including SREBP-1c, in a high fat diet model of non-alcoholic fatty liver disease. 33 …”

Section: Discussionmentioning

confidence: 99%

Metformin prevents hepatocellular carcinoma development by suppressing hepatic progenitor cell activation in a rat model of cirrhosis

DePeralta

Wei

Ghoshal

et al. 2016

Cancer

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“…Mice were administered metformin, 250 mg/kg/day in PBS (n=10 mice), or PBS alone (n=7 mice) as vehicle control via oral gavage. The metformin dose was selected based on published rodent modeling system precedents 19 , comparable to dosing required for insulin-resistant (type 2) diabetes management in humans (up to 35 mg/kg/day) as determined by allometric scaling 20 . Metformin therapy was initiated 3 days prior to, and terminated 14 days following, PPE infusion.…”

Section: Methodsmentioning

confidence: 99%

Metformin treatment status and abdominal aortic aneurysm disease progression

Fujimura

Xiong

Kettler

et al. 2016

Journal of Vascular Surgery

129

152

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Objectives In population-based studies performed on multiple continents over the past two decades, diabetes mellitus has been negatively associated with the prevalence and progression of abdominal aortic aneurysm (AAA) disease. We investigated the possibility that metformin, the primary oral hypoglycemic agent in use worldwide, may influence the progression of AAA disease Methods Pre-operative AAA patients with diabetes were identified from an institutional database. After tabulating individual cardiovascular and demographic risk factors and prescription drug regimens, odds ratios for categorical influences on annual AAA enlargement were calculated via nominal logistical regression. Experimental AAA modeling experiments were subsequently performed in normoglycemic mice to validate the database-derived observations, as well as suggest potential mechanisms of metformin-mediated aneurysm suppression. Results Fifty eight patients met criteria for study inclusion. Of 11 distinct classes of medication considered, only metformin usage was negatively associated with AAA enlargement. This association remained significant after controlling for gender, age, cigarette smoking status and obesity. The median enlargement rate in AAA patients not taking oral diabetic medication was 1.5 mm/year; by nominal logistic regression, metformin, hyperlipidemia, and age ≥70 years were associated with below median enlargement, whereas sulfonylurea therapy, initial aortic diameter ≥40 mm and statin usage were associated with above median enlargement. In experimental modeling, metformin dramatically suppressed the formation and progression, with medial elastin and smooth muscle preservation and reduced aortic mural macrophage, CD8 T cell and neovessel density. Conclusions Epidemiologic evidence of AAA suppression in diabetes may be attributable to concurrent therapy with the oral hypoglycemic agent metformin.

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“…On the other hand, studies using carcinogen-induced pancreas, oral, liver, skin, and prostate cancer rodent model systems showed much more profound suppression of tumor formation, which was associated with mTOR inhibition in some cases but independent of AMPK activation in other instances 39-44 . It should be noted that in the case of high-fat diet induced liver carcinogenesis, metformin treatment was effective during the early stages only, not by the time mice developed non-alcoholic fatty liver disease 43 . Of note, the positive studies in pancreas, liver, and skin model systems were performed under high-fat conditions, which may have optimized the opportunities for metformin efficacy.…”

Section: Animal Carcinogenesis Studiesmentioning

confidence: 99%

Repurposing old drugs to chemoprevention: the case of metformin

Heckman-Stoddard

Gandini

Puntoni

et al. 2016

Seminars in Oncology

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Multiple epidemiologic studies have documented an association between the anti-diabetic agent metformin and reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models or more recent epidemiological studies. The purpose of this paper is to examine metformin's chemopreventive potential by reviewing relevant mechanisms of action, preclinical evidence of efficacy, updated epidemiologic evidence after correction for potential biases and confounders, and recently completed and ongoing clinical trials. Although repurposing drugs with well described mechanisms of action and safety profiles is an appealing strategy for cancer prevention, there is no substitute for well executed late phase clinical trials to define efficacy and populations that are most likely to benefit from an intervention.

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Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 mice

Abstract: Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 mice. Am J Physiol Endocrinol Metab 305: E987-

Cited by 52 publications

References 46 publications

Metformin prevents hepatocellular carcinoma development by suppressing hepatic progenitor cell activation in a rat model of cirrhosis

Metformin prevents hepatocellular carcinoma development by suppressing hepatic progenitor cell activation in a rat model of cirrhosis

Metformin treatment status and abdominal aortic aneurysm disease progression

Repurposing old drugs to chemoprevention: the case of metformin

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