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Nitric oxide-donating aspirin (NO-Aspirin) suppresses lung tumorigenesis in vitro and in vivo and these effects are associated with modulation of the EGFR signaling pathway

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.