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Review
. 2013:2013:925804.
doi: 10.1155/2013/925804. Epub 2013 Dec 25.

Phytoagents for cancer management: regulation of nucleic acid oxidation, ROS, and related mechanisms

Wai-Leng Lee  1 , Jing-Ying Huang  2 , Lie-Fen Shyur  3
Affiliations
Review

Phytoagents for cancer management: regulation of nucleic acid oxidation, ROS, and related mechanisms

Wai-Leng Lee et al. Oxid Med Cell Longev. 2013.

Abstract

Accumulation of oxidized nucleic acids causes genomic instability leading to senescence, apoptosis, and tumorigenesis. Phytoagents are known to reduce the risk of cancer development; whether such effects are through regulating the extent of nucleic acid oxidation remains unclear. Here, we outlined the role of reactive oxygen species in nucleic acid oxidation as a driving force in cancer progression. The consequential relationship between genome instability and cancer progression highlights the importance of modulation of cellular redox level in cancer management. Current epidemiological and experimental evidence demonstrate the effects and modes of action of phytoagents in nucleic acid oxidation and provide rationales for the use of phytoagents as chemopreventive or therapeutic agents. Vitamins and various phytoagents antagonize carcinogen-triggered oxidative stress by scavenging free radicals and/or activating endogenous defence systems such as Nrf2-regulated antioxidant genes or pathways. Moreover, metal ion chelation by phytoagents helps to attenuate oxidative DNA damage caused by transition metal ions. Besides, the prooxidant effects of some phytoagents pose selective cytotoxicity on cancer cells and shed light on a new strategy of cancer therapy. The "double-edged sword" role of phytoagents as redox regulators in nucleic acid oxidation and their possible roles in cancer prevention or therapy are discussed in this review.

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Figures

Figure 1
Figure 1
Genetic heterogeneity following nucleic acid oxidation is a major driving force of cancer progression. ROS causes the oxidation of DNA bases. Subsequent base excision repair (BER) introduces genetic errors during the repair process, and the accumulation of these errors drives cancer progression.
Figure 2
Figure 2
Markers of oxidative DNA damage are elevated in cancer patients. ROS causes oxidative damage to biomolecules such as DNA, lipids, and proteins, and the resulting end products are often detrimental to normal cell physiological functions. As the result of DNA base oxidation, 8-oxo-guanine (8-oxoG) can serve as a biomarker of primary oxidative DNA damage. When lipids are attacked by ROS, secondary DNA damage arises due to malondialdehyde (MDA), the end production of lipid peroxidation that can covalently bind to guanine and form MDA-DNA adduct (M1dG). In human cancer patients, both 8-oxoG and M1dG are found to be elevated, suggesting a correlation between higher oxidative stress and cancer.
Figure 3
Figure 3
The source and clearance of ROS. (a) Three major origins of ROS. The sources of ROS can be roughly classified into three major categories: exogenous, endogenous, and transition metal ion-catalyzed. Exogenous sources of ROS can elicit radical chain reactions, contain/produce ROS, or stimulate enzymatic ROS production. Endogenous sources of ROS include the various enzymes that produce ROS as by-products or as signaling mediators or as antimicrobial agents during inflammation. Many of these enzymes can be activated by stimulation by cytokines and growth factors, such as NOX, LOX, XO, and MPO. Some CYPs are inducible and can be upregulated by environmental pollutants, dietary phytocompounds, or drugs. The transition metal ion-catalyzed Fenton-reaction produces highly reactive hydroxyl radical from hydrogen peroxide. (b) Layers of antioxidant defense. There are several layers of antioxidant defense. Basal level antioxidant defenses provide buffering capacity upon ROS challenge. Radical scavengers can directly quench ROS, and metal-chelating proteins can block ROS generation catalyzed by the Fenton or Fenton-like reactions. Further antioxidant capacity is provided by inducible antioxidant enzymes that are mostly under the regulation of Nrf2/ARE signaling (see Figure 4). ROS can oxidize the thiol group of amino acid residues leading to intermolecular or intramolecular disulfide bond formation. These disulfide bonds that are caused by oxidation can lead to structural/functional alteration of proteins. These disulfide bonds can be reduced by the glutathione system and the thioredoxin system allowing resumption of protein function. NADPH plays an indispensable role in the recycling of glutathione and thioredoxin, and therefore metabolic enzymes that are involved in NADPH generation also account for antioxidant defense.
Figure 4
Figure 4
Inducible antioxidant defense regulated by Nrf2/Keap1 and the antioxidant response element. Under normal physiological conditions, the transcription factor Nrf2 is sequestered in the cytosol by Keap1. Keap1 recruits ubiquitin ligase E3 which then ubiquitinates Nrf2 and directs it to the proteasome degradation pathway. The increased level of ROS promotes the dissociation of Nrf2 and Keap1, either via activation of kinases that phosphorylate Nrf2 or by oxidization of key cysteine residues that govern Keap1 activity. The dissociated Nrf2 is then translocated into the nucleus and binds to the antioxidant response element (ARE). ARE-regulated genes are then transcriptionally activated, including a panel of antioxidant enzymes or proteins, such as glutathione synthetase (GSS), glutathione reductase (GR), glutathione peroxidase (GPx), thioredoxin (TRX), thioredoxin reductase (TRR), and peroxiredoxin (PRX). These inducible antioxidant enzymes then provide further ROS clearance capacity and antioxidant defense mechanism to exert a cytoprotective effect.
Figure 5
Figure 5
Repair of oxidative DNA damage introduces genome heterogeneity and instability. ROS causes oxidation of DNA bases which then elicit base excision repair machineries. First, the oxidized base is cleaved by glycosylase leaving an apurinic/apyrimidinic site (AP site). Second, the AP site is recognized by AP endonuclease that cleaves the phosphodiester bonds to remove the AP nucleotide and create the single-strand break (SSB) intermediate. DNA polymerase then resynthesizes the missing part of the DNA and later DNA ligase seals the nick. The low fidelity of the translesion DNA polymerase increases the chance of mismatched base-pairing and thus, leads to accumulation of point mutations which creates genome heterogeneity.
Figure 6
Figure 6
Representative phytocompounds with redox regulation capability. There are four major types of phytocompounds that can modulate intracellular redox status: (A) phenolics, (B) terpenes, (C) vitamins, and (D) organosulfides. They show free radical scavenging, Nrf2/ARE activation, and/or facilitation of ROS production in cancer cells.
Figure 7
Figure 7
Role switches under different conditions—phytoagents function as both antioxidants and prooxidants in concert with transition metal ions. The level of transition metal ions determines whether a phyto-antioxidant ultimately functions as cytoprotective antioxidant or cytotoxic prooxidant. Under normal levels of transition metal ions, phytoantioxidants serve as radical scavengers and Nrf2/ARE activators that confer a cytoprotective effect that can be applied in chemoprevention. When the level of intracellular transition metal ion is high, such as in cancer cells, phytoantioxidants recycle the metal ions and thus facilitate ROS production through the Fenton or Fenton-like reactions. Otherwise, metal ions catalyze the cleavage of phytoagents and generate radical cleavage products that can cause ROS. Such a prooxidant effect further drives the redox-sensitive cancer cells to their antioxidant limit and leads to cytotoxicity that can be applied as a chemotherapeutic strategy. On the other hand, metal-chelating phytoagents reduce metal ion levels and thus block the ROS producing Fenton(-like) reaction and provide a cytoprotective effect.
Figure 8
Figure 8
Summary of mechanisms of action of phytoagents in chemoprevention and chemotherapeutics through modulating oxidative stress. In the presence of ferrous ions (or other transition metal ions), phytoagents recycle the metal ion and thus promote the Fenton reaction that generates the highly reactive hydroxyl radical from hydrogen peroxide. Such prooxidant effects of phytoagents in the presence of metal ion can overwrite their cytoprotective roles because the production of ROS may be faster than the induction of antioxidant defense. Hydrogen peroxide imposes oxidative damage on biomolecules, such as proteins, lipids, and DNA, and leads to protein carbonylation, lipid peroxidation, and DNA base oxidation, which can be prevented by phytoantioxidants. Phytoantioxidants can activate Nrf2/ARE signaling and thus transcriptionally upregulate a panel of antioxidant genes that can provide further antioxidant capacity. Glutathione synthetase (GSS) can raise the level of glutathione (GSH) which can reduce oxidative damage by scavenging hydroxyl radicals, which otherwise cause oxidative DNA damage and increase the chance of point mutation and genome instability during the DNA repair process while glutathione reductase (GR) recycles the oxidized form of GSH and maintains the level of the reduced form of GSH. Glutathione peroxidase (GPx), thioredoxin (TRX), and peroxiredoxin (PRX) can prevent oxidative insults on proteins and lipids.
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