Dietary diindolylmethane suppresses inflammation-driven lung squamous cell carcinoma in mice.
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 with 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 with mice treated with LPS alone, mice treated with NTCU plus LPS showed significantly increased expression of the inflammatory cytokines IL1α, IL6, 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 2,460 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.
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Jung Min
JM
Song
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Xuemin
X
Qian
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Fitsum
F
Teferi
Department of Pharmacology and Toxicology and Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
Jing
J
Pan
Department of Pharmacology and Toxicology and Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
Yian
Y
Wang
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota. kassi012@umn.edu.
Fekadu
F
Kassie
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002330:Carmustine / Q000031:analogs & derivatives / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007211:Indoles / Q000008:administration & dosage* / Q000737:chemistry; D007249:Inflammation / Q000188:drug therapy*; D008070:Lipopolysaccharides / Q000737:chemistry; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism
D016207:Cytokines; D007211:Indoles; D008070:Lipopolysaccharides; C572573:N-nitroso-tris-chloroethylurea; D016328:NF-kappa B; C016392:3,3'-diindolylmethane; D002330:Carmustine