Journal Article

Mechanisms of <i>N</i>-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points

Silvio De Flora, Alberto Izzotti, Francesco D'Agostini and Roumen M. Balansky

in Carcinogenesis

Volume 22, issue 7, pages 999-1013
Published in print July 2001 | ISSN: 0143-3334
Published online July 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.7.999
Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points

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Although smoking cessation is the primary goal for the control of cancer and other smoking-related diseases, chemoprevention provides a complementary approach applicable to high risk individuals such as current smokers and ex-smokers. The thiol N-acetylcysteine (NAC) works per se in the extracellular environment, and is a precursor of intracellular cysteine and glutathione (GSH). Almost 40 years of experience in the prophylaxis and therapy of a variety of clinical conditions, mostly involving GSH depletion and alterations of the redox status, have established the safety of this drug, even at very high doses and for long-term treatments. A number of studies performed since 1984 have indicated that NAC has the potential to prevent cancer and other mutation-related diseases. N-Acetylcysteine has an impressive array of mechanisms and protective effects towards DNA damage and carcinogenesis, which are related to its nucleophilicity, antioxidant activity, modulation of metabolism, effects in mitochondria, decrease of the biologically effective dose of carcinogens, modulation of DNA repair, inhibition of genotoxicity and cell transformation, modulation of gene expression and signal transduction pathways, regulation of cell survival and apoptosis, anti-inflammatory activity, anti-angiogenetic activity, immunological effects, inhibition of progression to malignancy, influence on cell cycle progression, inhibition of pre-neoplastic and neoplastic lesions, inhibition of invasion and metastasis, and protection towards adverse effects of other chemopreventive agents or chemotherapeutical agents. These mechanisms are herein reviewed and commented on with special reference to smoking-related end-points, as evaluated in in vitro test systems, experimental animals and clinical trials. It is important that all protective effects of NAC were observed under a range of conditions produced by a variety of treatments or imbalances of homeostasis. However, our recent data show that, at least in mouse lung, under physiological conditions NAC does not alter per se the expression of multiple genes detected by cDNA array technology. On the whole, there is overwhelming evidence that NAC has the ability to modulate a variety of DNA damage- and cancer-related end-points.

Keywords: AHH, arylhydrocarbon hydroxylase; AP-1, activator protein-1; ARE, antioxidant response elements; AsA, ascorbic acid; BITC, benzyl isothiocyanate; COX, cyclooxygenase; CS, cigarette smoke; CSC, cigarette smoke condensate; EGF, epidermal growth factor; ERK, extracellular signal-regulated kinase; G6PD, glucose 6-phosphate dehydrogenase; GSH, reduced glutathione; GST, GSH S-transferase; IKK, IκB kinase; IQ, 2-amino-3-methylimidazo[4,5-f]quinoline; ITCs, isothiocyanates; MAPC, mitogen activated protein kinase; mtDNA, mitochondrial DNA; NAC, N-acetyl-l-cysteine; NCE, normochromatic erythrocytes; NF-κB, nuclear factor-κB; NIK, NF-κB inducing kinase; NK, natural killer; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; NO, nitric oxide; •OH, hydroxyl radical; O2–, superoxide anion; 'O2, singlet oxygen; 8-OH-dG, 8-hydroxy-2′-deoxyguanosine; 8-oxo-dG, 8-oxo-2′-deoxyguanosine; PAM, pulmonary alveolar macrophages; PARP, poly(ADP ribose) polymerase; PCE, polychromatic erythrocytes; PEITC phenethyl isothiocyanate; 6PGD, 6-phosphogluconate dehydrogenase; PGE2, prostaglandin E2; PhIP, 2-amino-2-methyl-6-phenylimidazo[4,5-b]pyridine; PHITC, 6-phenylhexyl isothiocyanate; RB, retinoblastoma; ROS, reactive oxygen species; SFS, synchronous fluorescence spectrophotometry; STAT1, signal transducers and activator of transcription; TGF-β, tumor growth factor-β; TNF-α, tumor necrosis factor-α; TPA, 12-O-tetradecanoylphorbol 13-acetate; Trp-P-2, 3-amino-1-methyl-5H-pyrido[4,3-b]indole; TUNEL, TdT-mediated dUTP nick end labeling.

Journal Article.  14108 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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