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Selective inhibition by aspirin and naproxen of mainstream cigarette smoke-induced genotoxicity and lung tumors in female mice

  • Genotoxicity and Carcinogenicity
  • Published:
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Abstract

The role of nonsteroidal anti-inflammatory drugs (NSAIDs) in smoke-related lung carcinogenesis is still controversial. We have developed and validated a murine model for evaluating the tumorigenicity of mainstream cigarette smoke (MCS) and its modulation by chemopreventive agents. In the present study, the protective effects of the nonselective cyclooxygenase inhibitors aspirin and naproxen were investigated by using a total of 277 Swiss H neonatal mice of both genders. Groups of mice were exposed whole-body to MCS during the first 4 months of life, followed by an additional 3.5 months in filtered air in order to allow a better growth of tumors. Aspirin (1600 mg/kg diet) and naproxen (320 mg/kg diet) were given after weanling until the end of the experiment. After 4 months of exposure, MCS significantly enhanced the frequency of micronucleated normochromatic erythrocytes in the peripheral blood of mice, and naproxen prevented such systemic genotoxic damage in female mice. After 7.5 months, exposure of mice to MCS resulted in the formation of lung tumors, both benign and malignant, and in several other histopathological lesions detectable both in the respiratory tract and in the urinary tract. Aspirin and, even more sharply, naproxen significantly inhibited the formation of lung tumors in MCS-exposed mice, but this protective effect selectively occurred in female mice only. These results lend support to the views that estrogens are involved in smoke-related pulmonary carcinogenesis and that NSAIDs have antiestrogenic properties. The two NSAIDs proved to be safe and efficacious in the experimental model used.

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Abbreviations

AsA:

Acetylsalicylic acid or aspirin

COX:

Cyclooxygenase

CS:

Cigarette smoke

MCS:

Mainstream cigarette smoke

MN:

Micronucleated

NCE:

Normochromatic erythrocytes

NNK:

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone

References

  • Balansky R, Ganchev G, Iltcheva M et al (2007) Potent carcinogenicity of cigarette smoke in mice exposed early in life. Carcinogenesis 28:2236–2243

    Article  CAS  PubMed  Google Scholar 

  • Balansky R, Ganchev G, Iltcheva M et al (2009) Prenatal N-acetylcysteine prevents cigarette smoke-induced lung cancer in neonatal mice. Carcinogenesis 30:1398–1401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balansky R, Ganchev G, Iltcheva M et al (2010) Prevention of cigarette smoke-induced lung tumors in mice by budesonide, phenethyl isothiocyanate, and N-acetylcysteine. Int J Cancer 126:1047–1054

    CAS  PubMed  Google Scholar 

  • Balansky R, Ganchev G, Iltcheva M et al (2012a) Differential carcinogenicity of cigarette smoke in mice exposed either transplacentally, early in life or in adulthood. Int J Cancer 130:1001–1010

    Article  CAS  PubMed  Google Scholar 

  • Balansky R, Ganchev G, Iltcheva M et al (2012b) Inhibition of lung tumor development by berry extracts in mice exposed to cigarette smoke. Int J Cancer 131:1991–1997

    Article  CAS  PubMed  Google Scholar 

  • Balansky R, Ganchev G, Iltcheva M et al (2012c) Transplacental antioxidants inhibit lung tumors in mice exposed to cigarette smoke after birth: a novel preventative strategy? Curr Cancer Drug Targets 12:164–169

    Article  CAS  PubMed  Google Scholar 

  • Balansky R, Izzotti A, D’Agostini F et al (2014) Assay of lapatinib in murine models of cigarette smoke carcinogenesis. Carcinogenesis 35:2300–2307

    Article  PubMed  PubMed Central  Google Scholar 

  • Balansky R, Ganchev G, Iltcheva M et al (2015) Modulation by licofelone and celecoxib of experimentally induced cancer and preneoplastic lesions in mice exposed to cigarette smoke. Curr Cancer Drug Targets 15:188–195

    Article  CAS  PubMed  Google Scholar 

  • Bosetti C, Gallus S, La Vecchia C (2009) Aspirin and cancer risk: a summary review to 2007. Recent Results Cancer Res 181:231–251

    Article  CAS  PubMed  Google Scholar 

  • Camoirano A, Balansky RM, Bennicelli C (1994) Experimental databases on inhibition of the bacterial mutagenicity of 4-nitroquinoline 1-oxide and cigarette smoke. Mutat Res 317:89–109

    Article  CAS  PubMed  Google Scholar 

  • Cuzick J, Otto F, Baron JA et al (2009) Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol 10:501–507

    Article  CAS  PubMed  Google Scholar 

  • De Flora S, Izzotti A, D’Agostini F et al (2014) Rationale and approaches to the prevention of smoking-related diseases: overview of recent studies on chemoprevention of smoking-induced tumors in rodent models. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 32:105–120

    Article  PubMed  Google Scholar 

  • Harris RE, Chlebowski RT, Jackson RD et al (2003) Breast cancer and non-steroidal anti-inflammatory drugs: prospective research from the Women’s Health Initiative. Cancer Res 63:6096–6101

    CAS  PubMed  Google Scholar 

  • Horn SL, Fentiman IS (2010) The role of non-steroidal anti-inflammatory drugs in the chemoprevention of breast cancer. Pharmaceuticals 3:1550–1560

    Article  CAS  PubMed Central  Google Scholar 

  • International Agency for Research on Cancer (2012) A review of human carcinogens: personal habits and indoor combustions. IARC monographs on the evaluation of the carcinogenic risks to humans, vol 100, part E. IARC, Lyon

    Google Scholar 

  • Izzotti A, Balansky RM, Camoirano A, Cartiglia C, Longobardi M, Tampa E, De Flora S (2003) Birth-related genomic and transcriptional changes in mouse lung. Modulation by transplacental N-acetylcysteine. Mutat Res 544:441–449

    Article  CAS  PubMed  Google Scholar 

  • Izzotti A, Balansky R, D’Agostini F et al (2013) Relationships between pulmonary micro-RNA and proteome profiles, systemic cytogenetic damage and lung tumors in cigarette smoke-exposed mice treated with chemopreventive agents. Carcinogenesis 34:2322–2329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Izzotti A, Balansky R, D’Agostini F et al (2014) Modulation by metformin of molecular and histopathological alterations in the lung of cigarette smoke-exposed mice. Cancer Med 3:719–730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jalbert G, Castonguay A (1992) A effects of NSAIDs on NNK-induced pulmonary and gastric tumorigenesis in A/J mice. Cancer Lett 66:21–28

    Article  CAS  PubMed  Google Scholar 

  • Kelloff GJ, Crowell JA, Boone CW et al (1994) Clinical development plan: aspirin. J Cell Biochem Suppl 20:74–85

    Google Scholar 

  • Kreuzer M, Boffetta P, Whitley E et al (2000) Gender differences in lung cancer risk by smoking: a multicentre case-control study in Germany and Italy. Br J Cancer 82:227–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar A, Vishvakarma NK, Bharti AC et al (2012) Gender-specific antitumor action of aspirin in a murine model of a T-cell lymphoma bearing host. Blood Cells Mol Dis 48:137–144

    Article  CAS  PubMed  Google Scholar 

  • La Maestra S, Micale RT, De Flora S et al (2013) DNA damage in exfoliated cells and histopathological alterations in the urinary tract of mice exposed to cigarette smoke and treated with chemopreventive agents. Carcinogenesis 34:183–189

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee SH, Williams MV, Dubois RN et al (2005) Cyclooxygenase-2-mediated DNA damage. J Biol Chem 280:28337–28346

    Article  CAS  PubMed  Google Scholar 

  • Lubet RA, Steele VE, Juliana MM et al (2010) Screening agents for preventive efficacy in a bladder cancer model: study design, end points, and gefitinib and naproxen efficacy. J Urol 183:1598–1603

    Article  CAS  PubMed  Google Scholar 

  • Mahdi JG, Mahdi AJ, Bowen ID (2006) The historical analysis of aspirin discovery, its relation to the willow tree and antiproliferative and anticancer potential. Cell Prolif 39:147–155

    Article  CAS  PubMed  Google Scholar 

  • Malkinson AM (2004) Evidence that inflammation encourages pulmonary adenocarcinoma formation in mice: clinical implications. Chest 125(5 Suppl):154S–155S

    Article  PubMed  Google Scholar 

  • Mauderly JL, Gigliotti AP, Barr EB et al (2004) Chronic inhalation exposure to mainstream cigarette smoke increases lung and nasal tumor incidence in rats. Toxicol Sci 81:280–292

    Article  CAS  PubMed  Google Scholar 

  • Mazhar D, Gillmore R, Waxman J (2005) COX and cancer. QJM 98:711–718

    Article  CAS  PubMed  Google Scholar 

  • McCormack VA, Hung RJ, Brenner DR et al (2011) Aspirin and NSAID use and lung cancer risk: a pooled analysis in the International Lung Cancer Consortium (ILCCO). Cancer Causes Control 22:1709–1720

    Article  PubMed  Google Scholar 

  • McCormick DL, Phillips JM, Horn TL et al (2010) Overexpression of cyclooxygenase-2 in rat oral cancers and prevention of oral carcinogenesis in rats by selective and nonselective COX inhibitors. Cancer Prev Res 3:73–81

    Article  CAS  Google Scholar 

  • Meireles SI, Esteves GH, Hirata R Jr et al (2010) Early changes in gene expression induced by tobacco smoke: evidence for the importance of estrogen within lung tissue. Cancer Prev Res 3:707–717

    Article  CAS  Google Scholar 

  • Mollerup S, Berge G, Baera R et al (2006) Sex differences in risk of lung cancer: expression of genes in the PAH bioactivation pathway in relation to smoking and bulky DNA adducts. Int J Cancer 119:741–744

    Article  CAS  PubMed  Google Scholar 

  • Oh SW, Myung SK, Park JY et al (2011) Korean Meta-analysis (KORMA) Study Group. Aspirin use and risk for lung cancer: a meta-analysis. Ann Oncol 22:2456–2465

    Article  PubMed  Google Scholar 

  • Peng J, Xu X, Mace BE et al (2013) Estrogen metabolism within the lung and its modulation by tobacco smoke. Carcinogenesis 34:909–915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rothwell PM, Fowkes FG, Belch JF et al (2011) Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377:31–41

    Article  CAS  PubMed  Google Scholar 

  • Saini RK, Sanyal SN (2009) Chemopreventive effect of nonsteroidal anti-inflammatory drugs on 9,10-dimethylbenz[a]anthracene-induced lung carcinogenesis in mice. Oncol Res 17:505–518

    Article  CAS  PubMed  Google Scholar 

  • Smith CJ, Perfetti TA, King JA (2006) Perspectives on pulmonary inflammation and lung cancer risk in cigarette smokers. Inhal Toxicol 18:667–677

    Article  CAS  PubMed  Google Scholar 

  • Stabile LP, Siegfried JM (2003) Sex and gender differences in lung cancer. J Gend Specif Med 6:37–48

    PubMed  Google Scholar 

  • Stabile LP, Siegfried JM (2004) Estrogen receptor pathways in lung cancer. Curr Oncol Rep 6:259–267

    Article  PubMed  Google Scholar 

  • Steele VE, Rao CV, Zhang Y et al (2009) Chemopreventive efficacy of naproxen and nitric oxide-naproxen in rodent models of colon, urinary bladder, and mammary cancers. Cancer Prev Res 2:951–956

    Article  CAS  Google Scholar 

  • Suh N, Reddy BS, DeCastro A et al (2011) Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by suppressing the p65/β-catenin/cyclin D1 signaling pathway in rats. Cancer Prev Res 4:1895–1902

    Article  CAS  Google Scholar 

  • Takahashi H, Ogata H, Nishigaki R et al (2010) Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation. Cancer Cell 17:89–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Terry MB, Gammon MD, Zhang FF et al (2004) Association of frequency and duration of aspirin use and hormone receptor status with breast cancer risk. JAMA 291:2433–2440

    Article  CAS  PubMed  Google Scholar 

  • Xie M, Shan Z, Zhang Y et al (2014) Aspirin for primary prevention of cardiovascular events: meta-analysis of randomized controlled trials and subgroup analysis by sex and diabetes status. PLoS ONE 9:e90286

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu J, Yin Z, Gao W et al (2012) Meta-analysis on the association between nonsteroidal anti-inflammatory drug use and lung cancer risk. Clin Lung Cancer 13:44–51

    Article  CAS  PubMed  Google Scholar 

  • Yue W, Santen RJ, Wang JP et al (2003) Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis. J Steroid Biochem Mol Biol 86:477–486

    Article  CAS  PubMed  Google Scholar 

  • Zang EA, Wynder EL (1996) Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst 88:183–192

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the US National Cancer Institute (Contract #HHSN-2612012000151).

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Authors and Affiliations

  1. National Center of Oncology, Sofia, 1756, Bulgaria

    Roumen Balansky, Gancho Ganchev & Marietta Iltcheva

  2. Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132, Genoa, Italy

    Rosanna T. Micale, Sebastiano La Maestra, Chiara D’Oria & Silvio De Flora

  3. Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, 20892, USA

    Vernon E. Steele

Authors
  1. Roumen Balansky
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  2. Gancho Ganchev
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Correspondence to Silvio De Flora.

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Balansky, R., Ganchev, G., Iltcheva, M. et al. Selective inhibition by aspirin and naproxen of mainstream cigarette smoke-induced genotoxicity and lung tumors in female mice. Arch Toxicol 90, 1251–1260 (2016). https://doi.org/10.1007/s00204-015-1550-5

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  • DOI: https://doi.org/10.1007/s00204-015-1550-5

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