Although regular
aspirin use has been shown to lower the risk of
colorectal cancer, its efficacy against
lung cancer is weak or inconsistent. Moreover,
aspirin use increases the risk of
ulcers and stomach
bleeding. In this study, we determined the efficacy of
nitric oxide-donating
aspirin (
NO-Aspirin), a safer form of
aspirin in which the parent
drug is linked to a
nitric oxide-releasing moiety through a spacer, to suppress lung
tumorigenesis. Under in vitro conditions,
NO-Aspirin significantly reduced the proliferation and survival of tumorigenic bronchial cell line (1170) and
non-small cell lung cancer (NSCLC) cell lines (A549, H1650, H1975 and HCC827) and colony formation by NSCLC cells at sub- or low micromolar concentrations (≤1 µM for 1170 cells and ≤6 µM for NSCLC cells) in a COX-2 independent manner. These effects were paralleled by suppression of phospho-
epidermal growth factor receptor (EGFR), -STAT3, -Akt and -ERK and enhanced
caspase 3 and PARP cleavage. Among NSCLC cells, EGFR mutant cells (H1650, H1975 and HCC827) were more sensitive than cells expressing wild-type EGFR (A549) and H1650 cells were the most sensitive. Moreover,
NO-Aspirin sensitized H1650 and H1975 cells to the antiproliferative effects of
erlotinib, a
tyrosine kinase inhibitor. In in vivo studies using
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) +
lipopolysaccharide (LPS)-induced model of lung
tumorigenesis,
NO-Aspirin significantly reduced the number and size of lung
tumors, expression of phospho-EGFR and -Akt as well as the pro-inflammatory molecules TNF-α and
interferon-gamma. Overall, these results indicate the potential of
NO-Aspirin for the
chemoprevention of
lung cancer in high risk populations.