Journal Article

Modulation of apoptosis by cigarette smoke and cancer chemopreventive agents in the respiratory tract of rats

Francesco D'Agostini, Roumen M. Balansky, Alberto Izzotti, Ronald A. Lubet, Gary J. Kelloff and Silvio De Flora

in Carcinogenesis

Volume 22, issue 3, pages 375-380
Published in print March 2001 | ISSN: 0143-3334
Published online March 2001 | e-ISSN: 1460-2180 | DOI:
Modulation of apoptosis by cigarette smoke and cancer chemopreventive agents in the respiratory tract of rats

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Preclinical studies may elucidate the meaning of biomarkers applicable to epidemiologic studies and to clinical trials for cancer prevention. No study has explored so far the effect of cigarette smoke on apoptosis in vivo. We evaluated modulation of apoptosis in cells of the respiratory tract of smoke-exposed Sprague–Dawley rats both by morphological analysis and TUNEL method. In a first study, exposure of rats to mainstream cigarette smoke for either 18 or 100 consecutive days produced a significant and time-dependent increase in the proportion of apoptotic cells in the bronchial and bronchiolar epithelium. Oral N-acetylcysteine did not affect the background frequency of apoptosis but significantly and sharply decreased smoke-induced apoptosis. In a second study, exposure of rats to a mixture of sidestream and mainstream smoke for 28 consecutive days resulted in a >10-fold increase in the frequency of pulmonary alveolar macrophages undergoing apoptosis. Dietary administration of either 5,6-benzoflavone, 1,2-dithiole-3-thione or oltipraz did not affect the frequency of smoke-induced apoptosis, whereas phenethyl isothiocyanate produced a further significant enhancement. Again, N-acetylcysteine and its combination with oltipraz significantly decreased smoke-induced apoptosis. In both studies exposure to smoke resulted in a sharp increase of cells positive for proliferating cell nuclear antigen (PCNA), which was unaffected by the examined chemopreventive agents. These findings highlight the concept that modulation of apoptosis has diversified meanings. Different meanings (as explained in the following lines). First, the apoptotic process is triggered as a defense system against genotoxic agents, such as the components of cigarette smoke. The further induction produced by phenethyl isothiocyanate, favoring removal of damaged cells, represents an example of a detoxification mechanism. Inhibition of smoke-induced apoptosis by N-acetylcysteine should be interpreted as an epiphenomenon of antigenotoxic mechanisms, as shown in parallel studies evaluating modulation of DNA alterations in the respiratory tract of the same animals. Thus, it is important to discriminate between whether the opposite modulation of apoptosis is per se a protective mechanism or the beneficial outcome of other mechanisms inhibiting genotoxicity.

Keywords: 1,2-D3T, 1,2-dithiole-3-thione; 5,6-BF, 5,6-benzoflavone; BAL, bronchoalveolar lavage; CS, cigarette smoke; ECS, environmental cigarette smoke; NAC, N-acetylcysteine; OPZ, oltipraz or 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione; PAM, pulmonary alveolar macrophages; PCNA, proliferating cell nuclear antigen; PEITC, phenethyl isothiocyanate; TUNEL, TdT-mediated dUTP nick end labeling.

Journal Article.  5022 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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