Increased inducible nitric oxide synthase in lung carcinoma of smokers

Cancer. 2008 Jan 15;112(2):372-81. doi: 10.1002/cncr.23166.


Background: Cigarette smoking is well known to play an important role in the development of lung cancer. Inducible nitric oxide synthase (iNOS) can either promote or inhibit cell proliferation and growth, which makes its role in the development of malignant tumors controversial. The relation between cigarette smoking and iNOS in human lung cancer is unknown.

Methods: The study examined the levels of iNOS/NO in nonsmall-cell lung cancer (NSCLC) tissues of smokers and nonsmokers and in NSCLC cells (NCI-H23) treated by 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent tobacco-specific carcinogen.

Results: The level of iNOS/NO was significantly higher in lung cancer tissues of smokers than that of nonsmokers. Unlike iNOS/NO, the activity of caspase-3 was reduced in the former compared with the latter. The expression of the cleaved caspase-3 was deceased in NCI-H23 cells treated with S-Nitroso-N-acetylpenicillamine (SNAP), an NO donor, whereas treatment with NG-methyl-L-arginine (NMA), an NO inhibitor, caused an increase in cleaved caspase-3. Consistent with the change in caspase-3, SNAP treatment inhibited cell death induced by UCN01, a potent cell death-inducer. NMA treatment greatly enhanced the sensitivity of the cells to UCN01. Further, the cells treated by NNK showed an increase in iNOS protein, accompanied by an elevation of cell proliferation.

Conclusions: The study demonstrates that cigarette smoking promotes the level of iNOS/NO but suppresses the activity of caspase-3, which may lead to the proliferation and growth of lung cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Caspase 3 / analysis
  • Female
  • Humans
  • Lung Neoplasms / complications
  • Lung Neoplasms / enzymology*
  • Male
  • Middle Aged
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase Type II / biosynthesis*
  • Nitrosamines / toxicity
  • S-Nitroso-N-Acetylpenicillamine / pharmacology
  • Smoking / metabolism*
  • Staurosporine / analogs & derivatives
  • Staurosporine / pharmacology


  • Nitrosamines
  • Nitric Oxide
  • S-Nitroso-N-Acetylpenicillamine
  • 7-hydroxystaurosporine
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • Nitric Oxide Synthase Type II
  • Caspase 3
  • Staurosporine