Exposure routes: The pathologically related free radicals originate within the body as a product of normal aerobic metabolic processes and inflammatory reactions, but some environmental agents, such as radiation and pollutants, with diverse routes of exposure, can increase the production of free radicals.
Where found: Free-radical-generating agents are diverse, as are their sources. The most common are tobacco smoke, sunlight, X rays, and automobile exhausts. Others include the carcinogens benzene, inorganic arsenic compounds, cadmium compounds, aflatoxins, and asbestos.
At risk: Populations at highest risk are those with a low dietary intake of antioxidants or genetic deficiencies in antioxidant enzymes (for example, glutathione peroxidase) or deoxyribonucleic acid (DNA) repair mechanisms, along with tobacco smokers, people who spend a long time in areas of heavy traffic or who are directly exposed to sunlight, and those with chronic inflammatory conditions.
Etiology and symptoms of associated cancers: The carcinogenic potential of free radicals arises from their ability to damage DNA, modify proteins by oxidation, and induce lipid peroxidation. The most frequently found form of oxidative DNA damage is hydroxylation of purine and pyrimidine bases. Other consequences of free radical actions for DNA are the generation of strand brakes, deamination, and formation of etheno adducts. Oxidative modifications of proteins include nitration, nitrosylation, and acetylation, among others. In addition, one of the most damaging effects of free radicals is lipid peroxidation because of its self-propagating nature, which greatly affects the properties and functioning of cell membranes. Furthermore, lipid peroxidation products, such as the reactive aldehydes malondialdehyde and 4-hydroxynonenal, can damage DNA and proteins in the same way as free radicals.
DNA oxidative damage can cause mutations in cancer-related genes, such as tumor-suppressor genes or oncogenes, and lead to the initiation and progression of cancer. Likewise, carcinogenesis can be induced by post-translational oxidative modification of proteins involved in the regulation of cell growth, signal transduction pathways, DNA repair, or other mechanisms of cellular homeostasis. For instance, free radicals are known to induce the transcription of the proto-oncogenes
FOS (also known as c-fos), JUN (c-jun), and MYC (c-myc), which stimulate cell growth. Also, posttranslational oxidative modifications of TP53 (p53), a tumor-suppressor protein, can inhibit its antiproliferative activity. Lastly, free radicals can promote not only tumor growth but also tumor migration and metastasis, by activating matrix metalloproteinases and stimulating the release of vascular endothelial growth factor. A current view of free radical actions supports the notion that these species do not act in a purely stochastic manner but are second messengers in redox-sensitive mechanisms of regulation of gene expression and enzyme activity. Aberrant and sustained redox signaling in oxidative stress situations leads to pathological changes, including cancer.
History: The relevance of free radicals in biological systems was first proposed by Denham Harman in 1956 in his classic article “Aging: A Theory Based on Free Radical and Radiation Chemistry.” Harman viewed age-related diseases as the result of an accumulation of oxidative damage. In the same year, in vitro studies showing the ability of oxygen reactive species to induce chromosome fragmentation in the presence of iron suggested for the first time the hypothesis of free-radical-induced carcinogenesis. Since then, the concept has been extended and free radicals have been found to be involved in most pathological conditions.
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