Abstract
Chronic inflammation plays a key tumor-promoting role in lung cancer. Our previous studies in mice demonstrated that neutrophils are critical mediators of tumor promotion in methylcholanthrene (MCA)-initiated, butylated hydroxytoluene (BHT)-promoted lung carcinogenesis. In the present study we investigated the role of neutrophil myeloperoxidase (MPO) activity in this inflammation promoted model. Increased levels of MPO protein and activity were present in the lungs of mice administered BHT. Treatment of mice with N-acetyl lysyltyrosylcysteine amide (KYC), a novel tripeptide inhibitor of MPO, during the inflammatory stage reduced tumor burden. In a separate tumor model, KYC treatment of a Lewis Lung Carcinoma (LLC) tumor graft in mice had no effect on tumor growth, however, mice genetically deficient in MPO had significantly reduced LLC tumor growth. Our observations suggest that MPO catalytic activity is critical during the early stages of tumor development. However, during the later stages of tumor progression, MPO expression independent of catalytic activity appears to be required. Our studies advocate for the use of MPO inhibitors in a lung cancer prevention setting.
Highlights
Lung cancer remains the major cause of cancer-related death in the Western World [1,2,3,4,5]
Our previous studies demonstrated a key role for neutrophils in inflammation-promoted lung tumorigenesis [19]
Consistent with previous studies we observed an increase in neutrophil numbers and the neutrophil chemoattractant, keratinocyte-derived cytokine (KC)/chemokine (C-X-C motif) ligand 1 (Cxcl1), in bronchoalveolar lavage fluid (BALF) from female BALB/cByJ (BALB) mice three days after treatment with butylated hydroxytoluene (BHT) (Figure 1A,B)
Summary
Lung cancer remains the major cause of cancer-related death in the Western World [1,2,3,4,5]. Identification of molecular targets of prevention and evaluation of non-toxic agents in pre-clinical animal models of lung cancer is a necessary prerequisite to chemoprevention in humans. To model the role of lung inflammation in tumorigenesis, a 2-stage approach is often used. This involves single administration of the tobacco-related carcinogen 3-methylcholanthrene (MCA) to initiate tumorigenesis, followed by multiple administrations of the lung injury agent butylated hydroxytoluene (BHT) to promote tumorigenesis. The MCA/BHT model is a widely accepted tumor promoter and model of lung injury [11,15,17,18]. We previously reported that neutrophils (and not T lymphocytes) are critical mediators of lung tumor promotion by BHT [19]
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