Inflammatory conditions of the lung such as chronic obstructive pulmonary disease
(COPD) are known to increase lung cancer risk, particularly lung squamous cell carcinoma
(LSCC). In the present study, we developed a mouse model of inflammation-driven LSCC that
was induced by N-nitroso-trischloroethylurea (NTCU) and enhanced by lipopolysaccharide
(LPS), a potent proinflammatory agent contained in tobacco and tobacco smoke, and
determined the chemopreventive effects of BioResponse diindolylmethane (DIM) in the same
model. Compared to mice treated with NTCU alone, mice treated with the combination of NTCU
and LPS had a 9-fold increase in the number of bronchioles with LSCC. Also, compared to
mice treated with LPS alone, mice treated with NTCU plus LPS showed significantly
increased expression of the inflammatory cytokines IL-1α, IL-6, and TNFα
(all three increased about 7-fold). Parallel to the increased cytokine gene expression,
the NTCU plus LPS-treated group exhibited significantly enhanced activation of
NF-κB, STAT3, ERK, p-38, and Akt, expression of p53, COX-2, and Mcl-1, and
NF-κB- and STAT3-DNA binding in the lung. Dietary administration of DIM (10
µmol/g diet or 2460 ppm) to mice treated with NTCU plus LPS reduced the incidence
of LSCC by 2-fold, suppressed activation/expression of proinflammatory and procarcinogenic
proteins and NF-κB- and STAT3-DNA binding, but not the expression of cytokines and
p53. This study highlights the potential significance of our mouse model to identify
promising drugs or dietary agents for the chemoprevention of human LSCC and that DIM is a
very good candidate for clinical lung cancer chemoprevention trials.