Metformin prevents tobacco carcinogen--induced lung tumorigenesis

Cancer Prev Res (Phila). 2010 Sep;3(9):1066-76. doi: 10.1158/1940-6207.CAPR-10-0055. Epub 2010 Sep 1.

Abstract

Activation of the mammalian target of rapamycin (mTOR) pathway is an important and early event in tobacco carcinogen-induced lung tumorigenesis, and therapies that target mTOR could be effective in the prevention or treatment of lung cancer. The biguanide metformin, which is widely prescribed for the treatment of type II diabetes, might be a good candidate for lung cancer chemoprevention because it activates AMP-activated protein kinase (AMPK), which can inhibit the mTOR pathway. To test this, A/J mice were treated with oral metformin after exposure to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Metformin reduced lung tumor burden by up to 53% at steady-state plasma concentrations that are achievable in humans. mTOR was inhibited in lung tumors but only modestly. To test whether intraperitoneal administration of metformin might improve mTOR inhibition, we injected mice and assessed biomarkers in liver and lung tissues. Plasma levels of metformin were significantly higher after injection than oral administration. In liver tissue, metformin activated AMPK and inhibited mTOR. In lung tissue, metformin did not activate AMPK but inhibited phosphorylation of insulin-like growth factor-I receptor/insulin receptor (IGF-1R/IR), Akt, extracellular signal-regulated kinase (ERK), and mTOR. This suggested that metformin indirectly inhibited mTOR in lung tissue by decreasing activation of insulin-like growth factor-I receptor/insulin receptor and Akt upstream of mTOR. Based on these data, we repeated the NNK-induced lung tumorigenesis study using intraperitoneal administration of metformin. Metformin decreased tumor burden by 72%, which correlated with decreased cellular proliferation and marked inhibition of mTOR in tumors. These studies show that metformin prevents tobacco carcinogen-induced lung tumorigenesis and support clinical testing of metformin as a chemopreventive agent.

MeSH terms

  • Adenylate Kinase / metabolism
  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Carcinogens*
  • Carcinoma / chemically induced
  • Carcinoma / prevention & control*
  • Drug Evaluation, Preclinical
  • Female
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Injections, Intraperitoneal
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / prevention & control*
  • Metformin / administration & dosage
  • Metformin / blood
  • Metformin / pharmacology
  • Metformin / therapeutic use*
  • Mice
  • Nicotiana / adverse effects*
  • Nicotiana / chemistry
  • Nitrosamines
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Carcinogens
  • Hypoglycemic Agents
  • Nitrosamines
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • Metformin
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • Adenylate Kinase