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

Abstract

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.

Differentiation of normal and cancer cells induced by sulfhydryl reduction: biochemical and molecular mechanisms

“…19,20 The in vitro differentiating action of NAC reported for the first time in the present work is not related to its radical scavenging properties. Indeed, neither antiproliferative effect nor differentiation were induced by the paradigmatic scavenger Trolox C, supplemented to the cell growth medium at concentrations ranging from 0.1 to 0.5 mM.…”

Supplemental effect of varying L-cysteine concentrations on the quality of cryopreserved boar semen

“…Furthermore, L-cysteine also has the ability to reduce lipid peroxidation that produces free radicals, and thus protect spermatozoa from ROS [2,4,5]. Besides being active as a glutathione precursor, L-cysteine can also account for a protective effect in the extracellular milieu, primarily due to its nucleophilic and antioxidant properties [30]. …”

Effects of N‐acetylcysteine in an esophageal carcinogenesis model in rats treated with diethylnitrosamine and diethyldithiocarbamate

“…Moreover, experimental studies in vitro and in animal models as well as Phase II clinical trials have shown the ability of NAC to prevent genotoxicity and cancer through a broad variety of mechanisms. 15 NAC has been investigated previously for the ability to prevent tumors at various sites 15,16 but its effect was never assayed in esophageal carcinogenesis. …”

“…31 Although no epidemiological data are available, DEN should be regarded for practical purposes as if it were carcinogenic to humans, due to its documented carcinogenicity in all animal species tested after administration by various routes. 31 NAC, one of the most promising cancer chemopreventive agents, 15,16 failed to modulate the yield of liver tumors produced by the DEN ϩ DEDTC combination. NAC had been shown previously to be without effects on DEN-induced liver foci and hepatocellular adenomas in C3H mice, 32 whereas it was successful to decrease the number of ␥-GT-positive foci in 2-acetylaminofluorene-treated Sprague-Dawley rats.…”

“…33 In contrast, NAC exhibited some protective effects toward esophageal carcinogenesis induced by DEN ϩ DEDTC, consisting in a significant shift from severe to mild preneoplastic lesions and in an inhibition of tumor multiplicity. NAC displays a very broad range of protective mechanisms toward genotoxicity and carcinogenicity, 15 and may be expected to antagonize at various levels the esophageal carcinogenesis in the model under study. First of all, NAC is likely to interfere with the metabolic activation of DEN, because it was shown to inhibit CYP2E1 in mammalian cells and to lower the cytotoxicity of N-nitrosodimethylamine.…”