https://staff.blog.ui.ac.id/hsuryadi/files/2012/02/ROS_RNS.pdf

Free radicals and antioxidants in normal physiological functions and human disease

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

The development of cancer in humans and animals is a multistep process. The complex series of cellular and molecular changes participating in cancer development are mediated by a diversity of endogenous and exogenous stimuli. One type of endogenous damage is that arising from intermediates of oxygen (dioxygen) reduction - oxygen-free radicals (OFR), which attacks not only the bases but also the deoxyribosyl backbone of DNA. Thanks to improvements in analytical techniques, a major achievement in the understanding of carcinogenesis in the past two decades has been the identification and quantification of various adducts of OFR with DNA. OFR are also known to attack other cellular components such as lipids, leaving behind reactive species that in turn can couple to DNA bases. Endogenous DNA lesions are genotoxic and induce mutations. The most extensively studied lesion is the formation of 8-OH-dG. This lesion is important because it is relatively easily formed and is mutagenic and therefore is a potential biomarker of carcinogenesis. Mutations that may arise from formation of 8-OH-dG involve GC --> TA transversions. In view of these findings, OFR are considered as an important class of carcinogens. The effect of OFR is balanced by the antioxidant action of non-enzymatic antioxidants as well as antioxidant enzymes. Non-enzymatic antioxidants involve vitamin C, vitamin E, carotenoids (CAR), selenium and others. However, under certain conditions, some antioxidants can also exhibit a pro-oxidant mechanism of action. For example, beta-carotene at high concentration and with increased partial pressure of dioxygen is known to behave as a pro-oxidant. Some concerns have also been raised over the potentially deleterious transition metal ion-mediated (iron, copper) pro-oxidant effect of vitamin C. Clinical studies mapping the effect of preventive antioxidants have shown surprisingly little or no effect on cancer incidence. The epidemiological trials together with in vitro experiments suggest that the optimal approach is to reduce endogenous and exogenous sources of oxidative stress, rather than increase intake of anti-oxidants. In this review, we highlight some major achievements in the study of DNA damage caused by OFR and the role in carcinogenesis played by oxidatively damaged DNA. The protective effect of antioxidants against free radicals is also discussed.

Role of oxygen radicals in DNA damage and cancer incidence

https://www.cell.com/trends/biochemical-sciences/pdf/S0968-0004(10)00140-4.pdf

Regulation of autophagy by ROS: physiology and pathology

https://www.cell.com/trends/cell-biology/pdf/S0962-8924(07)00168-7.pdf

ROS, mitochondria and the regulation of autophagy

Acrolein-induced cell death: a caspase-influenced decision between apoptosis and oncosis/necrosis.

It is well established that fatty acid metabolites of cyclooxygenase, lipoxygenase (LOX), and cytochrome P450 are implicated in essential aspects of cellular signaling including the induction of programmed cell death Here we review the roles of enzymatic and non-enzymatic products of polyunsaturated fatty acids in controlling cell growth and apoptosis Also, the spontaneous oxidation of polyunsaturated fatty acids yields reactive aldehydes and other products of lipid peroxidation that are potentially toxic to cells and may also signal apoptosis Significant conflicting data in terms of the role of LOX enzymes are highlighted, prompting a re-evaluation of the relationship between LOX and prostate cancer cell survival We include new data showing that LNCaP, PC3, and Du145 cells express much lower levels of 5-LOX mRNA and protein compared with normal prostate epithelial cells (NHP2) and primary prostate carcinoma cells (TP1) Although the 5-LOX activating protein inhibitor MK886 killed these cells, another 5-LOX inhibitor AA861 hardly showed any effect These observations suggest that 5-LOX is unlikely to be a prostate cancer cell survival factor, implying that the mechanisms by which LOX inhibitors induce apoptosis are more complex than expected This review also suggests several mechanisms involving peroxisome proliferator activated receptor activation, BCL proteins, thiol regulation, and mitochondrial and kinase signaling by which cell death may be produced in response to changes in non-esterified and non-protein bound fatty acid levels Overall, this review provides a context within which the effects of fatty acids and fatty acid oxidation products on signal transduction pathways, particularly those involved in apoptosis, can be considered in terms of their overall importance relative to the much better studied protein or peptide signaling factors

Fatty acid oxidation and signaling in apoptosis.

Cellular fate is controlled by a number of factors within the cell, including an abundance of, and defenses against, free radicals generated both endogenously and exogenously Free radical species are involved in regulating various growth, differentiation and death processes including apoptosis Apoptosis is a preferred form of cell death because it is highly ordered resulting in the death of a cell with minimal effects on surrounding cells or tissues Radicals generated during apoptosis directly modulate signaling cascades by activating or inhibiting survival transcription factors (ie NF-kappa B and AP-1), or more indirectly affecting such signaling by changing the cellular redox status [ie glutathione (GSH) and thioredoxin (Trx)] At high levels, free radicals, including reactive oxygen species and various unwanted and harmful byproducts of reactions with tissue macromolecules, particularly lipids, can cause acute injury if not hindered by cellular antioxidants These antioxidant protective systems are not only involved in preventing stress, but also maintaining the normal functioning of specific transcription factors and the bcl proteins This review will discuss the association of reactive oxygen species with GSH, Trx and bcl proteins in apoptosis

Julie C. Kern

Papers

Acrolein-induced cell death: a caspase-influenced decision between apoptosis and oncosis/necrosis.

Fatty acid oxidation and signaling in apoptosis.

Free radicals and apoptosis: relationships with glutathione, thioredoxin, and the BCL family of proteins.

Effect of acrolein and glutathione depleting agents on thioredoxin

Fatty acid release and oxidation are factors in lipoxygenase inhibitor-induced apoptosis