Oxidative Stress in Prostate Cancer

Changing Research Concepts Towards a Novel Paradigm for Prevention and Therapeutics

A Paschos; R Pandya; W C M Duivenvoorden; J H Pinthus

Disclosures

Prostate Cancer Prostatic Dis. 2013;16(3):217-225. 

In This Article

Barriers and Limitations of Using Antioxidants in PC Prevention

Knowledge with respect to the mechanism of action of antioxidants in PC is incomplete, which limits the design of proper interventions. On the basis of the chemical, physical and biological properties of formed oxidants studied, we believe that the following questions demand pertinent answers to select the best antioxidative supplement for PC prevention. (a) Which are the predominant ROS species produced in PC? (b) What are the relative reactivities, including diffusion distance and destructive power, of the ROS formed in PC cells? (c) Assuming that the levels of antioxidative enzymes in PC are decreased, what is the qualitatively assessed ability of the key non-enzymatic antioxidants (ascorbic acid, carotenoids, vitamin E and thiols) to scavenge relevant ROS formed in PC? (d) Which conditions could possibly moderate physiological ROS production?

Different ROS exhibit different reactivity and they also vary in their ability to be scavenged by specific antioxidants.[2] It is estimated that in the presence of a nominal cellular GSH concentration of 2 mM, H2O2 can diffuse up to 1.5 mm from the source of origin. For ONOO this distance amounts to up to 50 μm and for other ROS not more than 20 μm, which matches the average diameter of a cell.[2] Assuming that the predominant ROS in prostate tissue are H2O2,[3,9] OH, ONOO and O2, molecules such as the lipophilic carotenoids and vitamin E forms are expected to have limited scavenging capacity as they are mainly protective against oxidative damage occurring in membranes and not directed against oxidative DNA or protein damage occurring in the aqueous phase of the cell. The two predominant non-enzymatic scavenging pathways in the aqueous phase of cells are the GSH (thiols) and ascorbate (vitamin C) pathways.[2] For the sake of completion, bilirubin[85] and uric acid,[86] two native small molecules of the human body, are also postulated to possess antioxidative capacities. As thiols (for example, GSH, cysteine, methionine, N-acetyl-cysteine) react with a wide range of oxidants, they more effectively manage ROS[87] produced in PC; however, as they easily undergo oxidation because of their high chemical reactivity, they are practically difficult to administer. For instance, the most prominent biogenic thiol cysteine becomes reduced only within the cell, while it is transported in oxidized form as cystin (dimeric cysteine linked by a disulfide bond) in the serum.[88] Similarly, reduced GSH oxidizes to a dimer (GS–SG) after an ROS-scavenging round and is enzymatically regenerated by GSH reductase. The reduction potential for this reaction is most likely delivered by the pentose-phosphate pathway whose metabolic status in PC still remains elusive. Interestingly, the GSH scavenging pathway intercepts O2, forming O2 and requires superoxide dismutase to detoxify the latter.[2] Conversely, thiol by-products (for example, thiyl radicals) potentially formed during the scavenging process may damage proteins by abstracting protons or by initiating lipid peroxidation. Ascorbic acid, a molecule with low reduction potential, is possibly a superior scavenger, as it reacts with a wide spectrum of oxidants, interconverts with the glutathione pathway and forms ascorbyl radicals, which are scavenged by ascorbate itself. Unfortunately, unlike thiols, although ascorbate scavenges O2 , it is ineffective towards H2O2. Along these lines, the synergistic combination of thiols and ascorbic acid may be favorable, as ascorbate could interrupt thiyl radicals and GSH-dependent O2 formation in the already superoxide dismutase-limited environment of PC. However, one major limitation occurs from the fact that the thiol pathway (especially GSH) requires components of the enzymatic antioxidant system (γ-glutamylcysteine synthetase, GSH synthetase and cystine transporters).

Prevention studies aiming to analyze the preventive synergistic effects of thiols (cysteine and methionine) with already studied antioxidants (carotenoids and vitamins E and C) could potentially be promising. The best line of defense against oxidants would still be a synergistically acting and fully functioning enzymatic and non-enzymatic antioxidant system. Therefore, interventions or treatments and conditions aiming to increase effectively the cells' catalase, superoxide dismutase and the GSH contents in combination with a healthy diet may be a promising strategy to prevent PC.

A major limitation of antioxidants for PC prevention is that antioxidants do not limit the continuous ROS production per se, but rather protect from the effects of acute ROS damage. The sustained production stream of cellular ROS is difficult to interrupt, as ROS are common by-products of the standard aerobic metabolism, and as such would possibly damage the metabolic integrity of the cell. Undeniably, a minimal amount of ROS (especially H2O2) is essential for the physiological function of cells, as it stimulates mitogenic signaling and influences many important standard protein functions.[1] Antioxidant prevention should therefore aim to diminish and not eradicate the ROS formed.

To become potent scavengers, the limited bioavailability of the active form of the carotenoids and vitamin E antioxidants has to be overcome and they have to be combined with vitamin C to be effective.[13] Lycopene, one molecule out of the plethora of carotenoids, mainly found in tomatoes, emerged to display significant protective effects in PC.[89] Frequent consumption of lycopene-containing food products may be especially beneficial in PC risk reduction, as shown in a large cohort of healthy men.[90] Vitamin E, among the group of lipophilc substances, is still under investigation as to which form is biologically active and the more potent antioxidant.[91] Surprisingly, the prominence of selenium in PC prevention poses a biochemical conundrum. Remarkably, the selenoprotein incorporation pathway in eukaryotes is highly complex and unique biochemically, as well as intricately regulated. Selenocysteine (Sec), the main biologically active form of selenium, is very likely only co-translationally incorporated in selenoproteins (Sec biosynthesis from serine on the tRNA(Sec) requires four enzymatic steps).[92] Therefore, it is questionable whether enzymatic antioxidative activity (eg glutathione peroxidase) is necessarily increased by simply administering selenium, selenomethionine or Sec. The peculiarity of Sec biosynthesis coheres with the observation that selenium taken alone in the SELECT study does not show any protection against PC. Furthermore, many of the non-enzymatic scavenging molecules (vitamin E, polyphenols and isoflavonoides) display pro-oxidant activities under certain physiological conditions,[93] which may possibly explain, at least in part, the observed procancerogenic effects of vitamin E when taken at a 400 IU.

Finally, a different level of limited efficacy stems from basic chemical and physical properties of the antioxidants (for example, lipophilicity versus hydrophilicity), which unavoidably limits the maximal achievable intracellular scavenger concentration in the prostatic tissue. The number of ROS-scavenging molecules actively transported across the membrane is minimal and possibly limited to small molecules, such as the thiols, cysteine and methionine, whereas the majority of vitamin antioxidants will cross the cell membrane barrier passively through diffusion, likely never reaching concentrations high enough for efficacy.

A provocative hypothesis for a method to reduce ROS production physiologically in PC cells is to induce ketone body (acetoacetate, β-hydroxybutyrate) metabolism.[94] In this metabolic pathway, the CoQ/CoQH2 ratio within the mitochondrion is altered causing a decrease in mitochondrial O2 and subsequent H2O2 production. Moreover, ketone bodies are suggested to display antioxidant capacity.[94] A simple means of initiating this metabolism is through dietary energy restriction with parallel adequate nutritional value and essential minerals and vitamins. Noteworthy, a ketogenic diet slows PC growth in animal models.[95] Whether the biological evidence to support this association is the accompanied reduction in ROS production, or the fact that prostate tissue only marginally utilizes glucose, remains to be determined.

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