Free radicals, metals and antioxidants in oxidative stress-induced cancer

Heavy metals are naturally occurring elements that have a high atomic weight and a density at least five times greater than that of water. Their multiple industrial, domestic, agricultural, medical, and technological applications have led to their wide distribution in the environment, raising concerns over their potential effects on human health and the environment. Their toxicity depends on several factors including the dose, route of exposure, and chemical species, as well as the age, gender, genetics, and nutritional status of exposed individuals. Because of their high degree of toxicity, arsenic, cadmium, chromium, lead, and mercury rank among the priority metals that are of public health significance. These metallic elements are considered systemic toxicants that are known to induce multiple organ damage, even at lower levels of exposure. They are also classified as human carcinogens (known or probable) according to the US Environmental Protection Agency and the International Agency for Research on Cancer. This review provides an analysis of their environmental occurrence, production and use, potential for human exposure, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity.

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Heavy metal toxicity and the environment.

The epigenomics of cancer.

Oxidative Stress, Inflammation, and Cancer: How Are They Linked?

Chemoprevention refers to the use of agents to inhibit, reverse or retard tumorigenesis. Numerous phytochemicals derived from edible plants have been reported to interfere with a specific stage of the carcinogenic process. Many mechanisms have been shown to account for the anticarcinogenic actions of dietary constituents, but attention has recently been focused on intracellular-signalling cascades as common molecular targets for various chemopreventive phytochemicals.

Cancer chemoprevention with dietary phytochemicals

Nickel is a widely distributed metal that is industrially applied in many forms. Accumulated epidemiological evidence confirms that exposures to nickel compounds are associated with increased nasal and lung cancer incidence, both in mostly occupational exposures. Although the molecular mechanisms by which nickel compounds cause cancer are still under intense investigation, the carcinogenic actions of nickel compounds are thought to involve oxidative stress, genomic DNA damage, epigenetic effects, and the regulation of gene expression by activation of certain transcription factors related to corresponding signal transduction pathways. The present review summarizes our current knowledge on the molecular mechanisms of nickel carcinogenesis, with special emphasis on the role of nickel induced reactive oxygen species (ROS) and signal transduction pathways.

Carcinogenic effect of nickel compounds.

Phenethyl isothiocyanate (PEITC) is a natural product that is among the most effective cancer chemopreventive agents known. Mechanistic studies indicate that the chemopreventive activity of PEITC is associated with its favorable modification of carcinogen metabolism and its induction of apoptosis. Here, we found that PEITC blocks tumor promoter (12-O-tetradecanoylphorbol-13-acetate or epidermal growth factor)-induced cell transformation in mouse epidermal JB6 cells, and this inhibitory activity on cell transformation is correlated with induction of apoptosis. Most importantly, apoptosis induction by PEITC occurs through a p53-dependent pathway. This was demonstrated not only by results that PEITC induction of p53 protein expression and p53-dependent transactivation but also by PEITC-induced apoptosis in p53 +/+ cells but not in p53 -/- cells. In contrast, PEITC induced apoptosis in cells with both normal or deficient sphingomyelinase activity. Our results demonstrate for the first time that p53 elevation is required for PEITC-induced apoptosis, which may be involved in its cancer chemopreventive activity.

https://cancerres.aacrjournals.org/content/canres/58/18/4102.full.pdf

Essential Role of p53 in Phenethyl Isothiocyanate-induced Apoptosis

Both water soluble and insoluble nickel compounds have been implicated in the etiology of human lung and nasal cancers. Water insoluble nickel compounds have been shown to enter cells by phagocytosis and are contained in cytoplasmic vacuoles, which are acidified thus accelerating the dissolution of soluble nickel from the particles. Using Newport Green, a dye that fluoresces when ionic nickel is bound, we have shown that following exposure (48-72 h) of human lung (A549) cells to NiS particles, most of the nickel is contained in the nucleus, while cells exposed to soluble NiCl2 exhibit most of the ions localized in the cytoplasm. This effect is consistent with previously published reports showing that short-term exposure of cells to crystalline nickel particles (1-3 days) is able to epigenetically silence target genes placed near heterochromatin, while similar short-term exposure to soluble nickel compounds are not able to induce silencing of genes placed near heterochromatin. However, a 3 week exposure of cells to soluble NiCl2 is also able to induce gene silencing. A similar effect was found in yeast cells where nickel was able to silence the URA-3 gene placed near (1.3 kb) a telomere silencing element, but not when the gene was placed farther away from the silencing element (2.0 kb). In addition to epigenetic effects, nickel compounds activate hypoxia signaling pathways. The mechanism of this effect involves the ability of either soluble or insoluble nickel compounds to block iron uptake leading to cellular iron depletion, directly affect iron containing enzymes, or both. This results in the inhibition of a variety of iron-dependent enzymes, such as aconitase and the HIF proline hydroxylases (PHD1-3). The inhibition of the HIF proline hydroxylases stabilizes the HIF protein and activates hypoxic signaling. Additional studies have shown that nickel and hypoxia decrease histone acetylation and increase the methylation of H3 lysine 9. These events are involved in gene silencing and hypoxia can also cause these effects in human cells. It is hypothesised that the state of hypoxia either by low oxygen tension or as a result of agents that signal hypoxia under normal oxygen tension (iron chelation, nickel and cobalt) results in low levels of acetyl CoA, which is a substrate for histone and other protein acetylation. This effect may in part be responsible for the gene silencing following nickel exposure and during hypoxia.

Nickel carcinogenesis: epigenetics and hypoxia signaling.

Inhibition of Activator Protein 1 Activity and Neoplastic Transformation by Aspirin

http://www.immunehealthscience.com/support-files/berries_cancer_study.pdf

Chuanshu Huang

Papers

Carcinogenic effect of nickel compounds.

Essential Role of p53 in Phenethyl Isothiocyanate-induced Apoptosis

Nickel carcinogenesis: epigenetics and hypoxia signaling.

Inhibition of Activator Protein 1 Activity and Neoplastic Transformation by Aspirin

Cancer prevention with freeze-dried berries and berry components