Abstract
Metal compounds such as arsenic, cadmium, chromium, cobalt, lead, mercury, and nickel are classified as carcinogens affecting human health through occupational and environmental exposure. However, the underlying mechanisms involved in tumor formation are not well clarified. Interference of metal homeostasis may result in oxidative stress which represents an imbalance between production of free radicals and the system’s ability to readily detoxify reactive intermediates. This event consequently causes DNA damage, lipid peroxidation, protein modification, and possibly symptomatic effects for various diseases including cancer. This review discusses predominant modes of action and numerous molecular markers. Attention is paid to metal-induced generation of free radicals, the phenomenon of oxidative stress, damage to DNA, lipid, and proteins, responsive signal transduction pathways with major roles in cell growth and development, and roles of antioxidant enzymatic and DNA repair systems. Interaction of non-enzymatic antioxidants (carotenoids, flavonoids, glutathione, selenium, vitamin C, vitamin E, and others) with cellular oxidative stress markers (catalase, glutathione peroxidase, and superoxide dismutase) as well as certain regulatory factors, including AP-1, NF-κB, Ref-1, and p53 is also reviewed. Dysregulation of protective pathways, including cellular antioxidant network against free radicals as well as DNA repair deficiency is related to oncogenic stimulation. These observations provide evidence that emerging oxidative stress-responsive regulatory factors and DNA repair proteins are putative predictive factors for tumor initiation and progression.
Highlights
A number of studies have been conducted to investigate adverse effect of various metallic nanoparticles or nanomaterials on induction of free radicals as well as their modes of action both in vitro and in vivo [23,24,25,26,27]. These findings indicate several types of DNA damage, including generation of micronuclei, formation of DNA adduct (8-hydroxy-2-deoxyguanosine), and chromosomal aberrations
The p53 protein with Cys3His1-typed zinc finger domain has an important role in DNA repair through the nucleotide excision repair (NER) and genomic stability [87]. p53 controls a number of key events to induce either
Understanding the mechanisms underlying toxicity initiated by diverse carcinogenic metals and metallic nanoparticles is of great concern
Summary
Metal compounds are found throughout the environment. Industrial applications contribute significantly to human metal exposure. Some metals, including arsenic, cadmium, chromium, cobalt, lead, mercury, and nickel have been classified as human carcinogens or considered to be human carcinogens by the International Agency for Research on Cancer and by the German MAK Commission. Their carcinogenic potentials are predominantly dependent on oxidation state, solubility, and complex form. (2) interference with DNA repair systems, resulting in genomic instability; and (3) interruption of cell growth and proliferation via signaling pathways and dysregulation of oncogenes or tumor suppressor genes [1] These possible common mechanisms of metal-induced carcinogenicity with unique discrepancies regarding to specific metals are discussed in more detail
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