Dietary Diindolylmethane Suppresses Inflammation-Driven Lung Squamous Cell Carcinoma in Mice

Abstract

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.

NLRP3 inflammasome activation involved in LPS and coal tar pitch extract‐induced malignant transformation of human bronchial epithelial cells

“…As far as we know, this was the first time to report inflammation‐related lung cancer model in vitro. Indeed, Song et al, established inflammation‐driven lung tumor mouse models using N‐nitroso‐trischloroethylurea (NTCU) or 4‐(methyl‐nitrosoamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) and LPS, but these models were set up in vivo. However, in vitro model regarding the inflammation‐associated lung cancer was lacking, and our study provided a suitable model for exploring the mechanisms of inflammation‐related lung cancer in vitro.…”

“…In recent years, the theory of “inflammation and cancer” has gradually attracted people's attention, and the inflammatory microenvironment has been regarded as “seventh hallmark of cancer.” Since lung is an organ that communicates directly with the outside world, it is easily exposed to environmental pollutants and pathogenic microorganisms to form inflammatory microenvironment . Although studies have confirmed that the sustained existence of chronic inflammation in the lung is a major driving force for the development of lung cancer, the molecular mechanism that chronic inflammation promotes lung cancer has not yet been elucidated.…”

“…Lipopolysaccharide (LPS), a major component of Gram‐negative bacteria, is widespread in tobacco smoke, dust, and the air, which is easy to inhale into the lungs . In addition, certain Gram‐negative bacilli such as Escherichia coli and Klebsiella pneumoniae are “timed bacteria” of lungs, and a large amount of LPS will be released into lungs when the micro‐ecological system formed by these “timed bacteria” is out of tune.…”

Harnessing the Power of Cruciferous Vegetables: Developing a Biomarker for Brassica Vegetable Consumption Using Urinary 3,3′-Diindolylmethane

“…(5–10) Both I3C and DIM possess strong effects in vitro and in-vivo against cancers of the lung, colon, prostate, and breast. (11–14) Mice gavaged with NNK and then treated with I3C or DIM developed significantly fewer lung tumors compared to controls. (13, 15, 16) In a placebo-controlled clinical trial, I3C taken for 12 weeks resulted in regression of cervical intraepithelial neoplasia in approximately half of the 17 women randomized to either 200 mg or 400 mg daily compared to placebo.…”

A comparative microarray analysis identifies a conserved gene expression signature between airway injury and lung cancer

“…Recently, genetically engineered mouse models have demonstrated that endogenous airway stem cells function as the cell-of-origin for murine lung cancer 3,12,13 . In these models, it is notable that the incidence, speed, and severity of lung tumours are all increased following lung injury and the presence of a pro-inflammatory microenvironment 14,15 . These results suggest that conserved, endogenous signalling pathways responsible for lung injury outcomes may additionally regulate lung tumorigenesis.…”