Clinical Study of Aspirin and Zileuton on Biomarkers of Tobacco-Related Carcinogenesis in Current Smokers
by
, , , , and
Linda L. Garland
1,2,*, 
José Guillen-Rodriguez
2,
Chiu-Hsieh Hsu
2,
Lisa E. Davis
3,
Eva Szabo
4,
Christopher R. Husted
5,
Hanqiao Liu
5,
Ashley LeClerc
6,
Yuriy O. Alekseyev
6,
Gang Liu
5,
Julie E. Bauman
1,2,7,
Avrum E. Spira
5,
Jennifer Beane
5,
Malgorzata Wojtowicz
4 and
H.-H. Sherry Chow
2 1
Department of Medicine, University of Arizona, Tucson, AZ 85724, USA
2
University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
3
College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA
4
Division of Cancer Prevention, National Cancer Institute, Bethesa, MD 20892, USA
5
Section of Computational Biomedicine, Department of Medicine, School of Medicine, Boston University, Boston, MA 02118, USA
6
Department of Pathology and Laboratory Medicine, School of Medicine, Boston University, Boston, MA 02118, USA
7
Division of Hematology/Oncology, Department of Medicine, George Washington (GW) University and GW Cancer Center, Washington, DC 20037, USA
*
Author to whom correspondence should be addressed.
Cancers 2022, 14(12), 2893; https://doi.org/10.3390/cancers14122893
Submission received: 20 April 2022
/
Revised: 24 May 2022
/
Accepted: 25 May 2022
/
Published: 11 June 2022
(This article belongs to the Section Cancer Epidemiology and Prevention)
Simple Summary
Aspirin and related drugs with anti-inflammatory effects have lung cancer prevention effects in laboratory studies and through their use in populations at risk for lung cancer. We studied aspirin plus zileuton compared to two placebo pills for 3 months in smokers. We studied genes associated with lung cancer, smoking, and lung disease. We used nasal swabs to collect nasal cells that were smoke exposed to look for changes in these genes. We found that most of the gene panels in the nasal cells related to smoking and lung cancer lung disease did not change in a favorable way, but we did see a favorable change in a gene panel representing abnormal squamous cells that may progress to lung cancer. We think this finding is of interest and can be studied further using deep lung biopsies to understand if this drug effect occurs where squamous cell lung cancer actually starts.
Abstract
The chemopreventive effect of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on lung cancer risk is supported by epidemiologic and preclinical studies. Zileuton, a 5-lipoxygenase inhibitor, has additive activity with NSAIDs against tobacco carcinogenesis in preclinical models. We hypothesized that cyclooxygenase plus 5-lipoxygenase inhibition would be more effective than a placebo in modulating the nasal epithelium gene signatures of tobacco exposure and lung cancer. We conducted a randomized, double-blinded study of low-dose aspirin plus zileuton vs. double placebo in current smokers to compare the modulating effects on nasal gene expression and arachidonic acid metabolism. In total, 63 participants took aspirin 81 mg daily plus zileuton (Zyflo CR) 600 mg BID or the placebo for 12 weeks. Nasal brushes from the baseline, end-of-intervention, and one-week post intervention were profiled via microarray. Aspirin plus zilueton had minimal effects on the modulation of the nasal or bronchial gene expression signatures of smoking, lung cancer, and COPD but favorably modulated a bronchial gene expression signature of squamous dysplasia. Aspirin plus zileuton suppressed urinary leukotriene but not prostaglandin E2, suggesting shunting through the cyclooxygenase pathway when combined with 5-lipoxygenase inhibition. Continued investigation of leukotriene inhibitors is needed to confirm these findings, understand the long-term effects on the airway epithelium, and identify the safest, optimally dosed agents.
Keywords:
lung cancer; cancer prevention; aspirin; prostaglandin; zileuton; leukotriene
