Research reveals how metformin reduces HCC risk

For every year that a patient with diabetes takes metformin, their risk for hepatocellular carcinoma (HCC) reduces, say the authors of a study that also sheds light on the cellular pathway it uses.

Although diabetes patients are at a two to three times greater risk for HCC, metformin is established to have a protective role. However, the dose-dependent effect of metformin has not been clarified and the cellular mechanism for its antitumor action has not been explored.

"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," say Chun-Ying Wu (National Yang-Ming University, Taipei, Taiwan) and colleagues.

Data on 97,430 HCC patients and 194,860 age-, gender- and physician date-matched controls were taken from the National Health Insurance Research Database, which includes health data for most of the Taiwanese population.

Reporting in Gut, researchers found that metformin use led to a 21% decrease in the risk for HCC in patients with diabetes and that it does so in a dose-dependent manner. For each year patients took metformin, their risk for developing the cancer declined by 7%.

Furthermore, studying hepatoma cells in vitro, metformin was found to increase the proportion of cells in the G0/G1 phases from 27% to 49% in HepG2 cells and from 46% to 75% in Hep3B cells.

Both pharmaceutical inhibition and genetic knockdown of adenosine monophosphate-activated protein kinase (AMPK) - an enzyme activated by metformin, leading to reduced liver glucose production and reduced insulin resistance - prevented metformin from inducing G0/G1 cell cycle arrest.

Additionally, when LKB1, the upstream kinase of AMPK, was knocked down this also inhibited AMPK phosphorylation by metformin, suggesting that metformin-induced AMPK phosphorylation is via LKB1.

In addition to its role in reducing the risk for HCC, the authors suggest that metformin may enhance its treatment, noting that a combination of doxorubicin and metformin significantly reduced cell viability in hepatoma cells, and reduced tumor growth in a mouse model.

The authors believe this evidence could lead to a new role for the drug outside the scope of diabetes: "AMPK activation by metformin, a generally considered 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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