In a nationwide study, researchers evaluated the effects of metformin on cell proliferation and cycle in the HepG2 and Hep3B hepatoma cell lines of 97,430 patients with hepatocellular carcinoma (HCC) and 194,860 matched controls.
Patients with HCC were found to be at increased risk for diabetes (OR=2.29, 95% CI, 2.25-2.35), which was diagnosed in 22,047 patients with HCC (22.6%) and 25,773 controls (13.2%). HBV, HCV, cirrhosis and alcoholic liver disease were all more common among patients with HCC. An association was established between metformin use and decreased HCC risk among patients with diabetes (adjusted OR=0.79, 95% CI, 0.75-0.83). This effect was found to be dose-dependent, with a 7% reduction in risk for each year of use (adjusted OR=0.93, 95% CI, 0.91-0.94).
Multivariate analysis indicated associations between metformin use and reduced HCC risk among diabetics in almost all subgroups, according to age, gender, duration of illness, insulin use and presence of cirrhosis, among other factors, but not among patients with HBV or HCV, or those using thiazolidinediones.
MTS test results indicated that metformin decreased cell viability and suppressed cell growth and colony formation in HepG2 and Hep3B hepatoma cell lines. Cell growth was inhibited regardless of p53 functionality. Flow cytometric analysis indicated that metformin increased cell population from 27.08% to 48.82% in HepG2 cells and from 46.15% to 74.79% in Hep3B cells in the G0/G1 phase. The decrease in cell viability and increase in population were both found to be dose-dependent, but an 80mM metformin dose caused apoptosis in both cell lines.
"Diabetic patients are associated with a higher HCC risk, which is attenuated by the use of metformin in a dose-dependent and duration-dependent manner," the researchers wrote. "To the best of our knowledge, this is the first time that metformin has been demonstrated to inhibit cell growth through cell cycle G0/G1 arrest in hepatoma cell lines.… Metformin, generally considered a safe, well-tolerated and relatively inexpensive drug for type 2 diabetes, may represent a new strategy to improve treatment of hepatoma."
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