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

Abstract

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.

The combination of metformin and 2‐deoxyglucose significantly inhibits cyst formation in miniature pigs with polycystic kidney disease

“…Notably, neither metformin nor 2DG has exhibited significant adverse side effects in the clinic (Lalau and Race, 1999;Dwarakanath et al, 2009;Stein et al, 2010). Metformin and 2DG have been studied in Phase I and II clinical studies in cancer patients (Cheong et al, 2011;DePeralta et al, 2016;Menamin et al, 2016). Previous studies have shown that polycystic kidney cells are similar to tumour cells.…”

Molecular magnetic resonance imaging accurately measures the antifibrotic effect of EDP‐305, a novel farnesoid X receptor agonist

“…Real‐time quantitative polymerase chain reaction was performed on whole liver and ileum samples from treated and imaged animals 24. Taqman primer sequences (Life Technologies, Carlsbad, CA) can be found in the http://onlinelibrary.wiley.com/doi/10.1002/hep4.1193/full.…”

Diabetes mellitus increases the risk of hepatocellular carcinoma in treatment-naïve chronic hepatitis C patients in China

“…However, our results conflicted with previous studies. [40,43,44] The reason might be that the patients included in our study were treatment-naïve therefore metformin might not improve responses to antiviral treatment. Second, a side effect of metformin is liver injury which had been reported in previous studies.…”