Review Article

A Potential Application of Antioxidants in Managing Cancer Progression

Zhi-Gang Jiang*, Hossein A Ghanbari
Panacea Pharmaceuticals, Inc, 209 Perry Parkway, Suite 13, Gaithersburg, MD 20877, USA
*Corresponding author:

Zhi-Gang Jiang, Panacea Pharmaceuticals, Inc, 209 Perry Parkway, Suite 13, Gaithersburg, MD 20877, USA, Phone: 240-454-8026; E-mail: zgjiang@panaceapharma.com

Keywords:

Age-related diseases, Antioxidants, Cancer, Neuroprotection, Precision medicine, Redox, Senescence

Abbreviations:

AD: Alzheimer’s disease, Akt: Protein Kinase B, ASX: Astaxanthin, ATBC: α-Tocopherol, β-Carotene, ATP: Adenosine triphosphate, CARET: β-Carotene and Retinol Efficacy Trial, CAT: Catalase, CDK: Cyclin-dependent kinases, CNS: Central nervous system, CoQ: Coenzyme Q, COX-2: Cyclooxygenase 2, CSE: Cigarette smoke extract, DETAPAC: Diethylenetriaminepentaacetic acid, EDTA: Ethylenediaminetetraacetic acid, ECGA: (-)-epigallocatechin-3-gallate, Erk 1/2: Extracellular- regulated kinase 1/2, 5-FU: 5-Fluorouracil, GPx: Glutathione peroxidase, GR: Glutathione reductase, GSH: Glutathione, GSSG: Glutathione disulfide, GTC: Green tea catechin, H2O2: Hydrogen peroxide, HBV: Hepatitis B virus, HBx: HBV X protein, HCC: Hepatocellular carcinoma, HCV: Hepatitis C virus, HG-PIN: High-grade prostate intraepithelial neoplasia, HIF-1α: Hypoxia inducible factor 1 alpha HO-1: Heme oxygenase 1, I3C: Indole-3-carbinol, K-Ras: Kirsten rat sarcoma viral oncogene homolog, LPS: Lipopolysaccharide, MAPK: Mitogen-activated protein kinase, MMPs: Matrix metalloproteinases, MTX: Methotrexate, NAC: N-acetylcysteine, NAFLD: Nonalcoholic fatty liver disease, NASH: Nonalcoholic steatohepatitis, NF-Kb: Nuclear factor-Κb, NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, O2.-: Superoxide anion, .OH: Hydroxyl radicals, 8-OHdG: 8-hydroxydeoxygnaunosine, OS: Oxidative stress, PGE2: Prostaglandin E2, PI3k: Phosphatidylinositol-3-Kinase, pIκBα: Phospho-Inhibitory Subunit of NF Kappa B Alpha, pRB: Retinoblastoma protein, pSTAT3: phospho-Signal transducer and activator of transcription 3, RCC: Renal cell carcinoma, REDD1: Regulated in development and DNA damage response 1, RNS: Reactive nitrogen species, ROS: Reactive oxygen species, Sil: Silibinin, SOD: Superoxide dismutase, TIMP: Tissue inhibitor of metalloproteinase, TR: Thioredoxin reductase, TRX: Thioredoxin, TRXO: Oxidized thioredox, VEGF: Vascular endothelial growth factor.

During the lifetime, people are often exposed to hazard environments, which results in accumulations of reactive oxygen species (ROS) and ROS-induced molecular damage in the body, and leads age-associated disorders, such as cardiovascular diseases, neurodegenerative diseases, cancer, etc. Although a central role of ROS in the etiology of these diseases is well accepted and antioxidant treatment shows great efficacies in preclinical studies, antioxidative therapies have been generally disappointing in clinical investigations. The contradictory results between preclinical and clinical studies have impacted development of antioxidant as interferential drug against the age-related diseases. This review article focuses a potential application of antioxidants in cancer prevention, therapy and adjuvant therapy, and emphasizes the controversial results with a hope of providing future attention in drug development process.

Age-associated diseases are those that occur with increasing frequency following senescence. Typically, these disorders, such as Alzheimer’s disease (AD), atherosclerosis, and majority of cancers, only appear in older population, rather than young ages. It is well accepted that accumulations of reactive oxygen species (ROS) and ROS-induced molecular damages mediate those age-associated diseases [1].

In aerobic respiration, O2 is converted into H2O on the mitochondrial respiratory chain while glucose is converted into human essential energy form adenosine triphosphate (ATP) via a coupling Krebs cycle, a process of oxidative phosphorylation. Under normal condition, 1%–2% of electrons leak from the mitochondrial electron transport chain and form superoxide anion O2.− via reduction of O2 by cycling the ubiquinol in the inner mitochondrial membrane [2]. O2.− is also enzymatically produced in endoplasmic reticulum (ER), plasma membrane and cytoplasm [3]. O2.− can be transformed through enzyme activity [superoxide dismutase, catalase (CAT), myeloperoxidase] into other forms of ROS, including hydrogen peroxide (H2O2), and hydroxyl radicals (.OH). A growing body of evidence in recent years has revealed that ROS at low/moderate concentrations play important roles in maintenance of body defenses and normal physiological functions, and involve a number of cellular signaling pathways in controlling cell survival, migration and proliferation [3].

However, excessive ROS in the body will cause and accelerate age-associated diseases. The Molecules that inhibit the oxidation of other molecules and removes oxidized molecules are named antioxidants (AOs). To control ROS within physiological level, enzymatic and non-enzymatic systems are both present in the body (see Table 1). The former consists of superoxide dismutase (SOD), CAT, thioredoxin reductase (TR), and glutathione peroxidase (GPx), and the later includes glutathione (GSH) and thioredoxin (TRX). In the cell, SOD first converts O2.- into H2O2, and then CAT enzymatically converts H2O2 is into H2O and O2. In the GSH buffer system, GPx converts H2O2 into H2O and O2 when it converts GSH into its oxidized disulfide form -glutathione disulfide (GSSG). GSSH is then reduced by glutathione reductase (GR) to regenerate GSH for reuse. In the TRX buffering system, the TRX in reduced status (TRXR) is oxidized into oxidized thioredox (TRXO) during the degradation of H2O2 and then reduced by TR. In addition to the enzymatic defense systems, the human body also uses non-enzymatic antioxidants to limit over-accumulation of ROS (see Table 1). These molecules mainly work as free radical scavengers or precursors for synthesis of the scavengers. The most important molecule among non-enzymatic antioxidants is GSH. GSH is highly abundant in the cytoplasm, nuclei and mitochondria. GSH reacts with a radical and becomes a thiyl radical itself. The newly-generated thiyl radicals dimerize to form the non-radical product oxidized GSH, GSSG. GSH in the nucleus maintains the redox state of sulfhydryls of critical proteins for DNA repair and gene expression [3].

Plants and their extractions also contain variety of antioxidants (Table 1), which may be used as food supplement to maintain ROS balance in the body. The antioxidants mainly act as free radical scavengers. In addition, divalent metal and heavy metals are actively involved in ROS production. Therefore, ROS level can indirectly be controlled by metal binding proteins and metal chelators, such as transferrin, ferritin, Desferal, diethylenetriaminepentaacetic acid (DETAPAC), ethylenediaminetetraacetic acid (EDTA), etc., which is not included in Table 1

 

Enzymatic

Antioxidants

Mechanism (Resource)

References

 Catalase (CAT)

Remove H2O2

Li et al., 2013 [3]

 Glutathione peroxidase (GPx)

Remove H2O2

Li et al.,2013 [3]

 Glutathione reductase (GR)

Reduce GSSH to GSH

Li et al., 2013 [3]

Superoxide dismutase (SOD)

Remove O2.-

Li et al., 2013 [3]

 Thioredoxin reductase (TR)

Reduce TRXO to TRX

Li et al., 2013 [3]

Non-enzymatic

Bilibrubin

Inhibit free radical chain reactions

McDonagh, 1990 [87]

 -

Reactive nitrogen species scavenger

Mancuso et al., 2006 [88]

Coenzyme Q (CoQ10)

Free radical scavenger

Yamamoto, 2016, [89]

Estrogen

Inhibit H2O2 production

Borrás et al., 2010 [90]

Glutamine

Precursor of GSH

Yu et al., 1999 [91]

Glutathione (GSH)

Free radical scavenger

Li et al., 2013 [3]

Methionine

Precursor of cysteine

Shan et al., 1989 [92]

Melatonin

Scavenge free radial; reduce electron leaking

Reiter et al., 2003 [93]

Pyruvate

 Inhibit O2.- formation

Bassenge et al., 2000 [94]

Taurine

Preserve respiratory chain and antioxidases     

Menzie et al., 2013 [95]

Vitamin C (L-ascorbic acid)

Free radical scavenger (citrus fruit)

Niki, 1987 [96]

Vitamin E (α-tocopherol)

Free radical scavenger (citrus fruit)

Niki, 1987 [96]

Food suppl.   

Astaxanthin (ASX)

Scavenger (in Haematococcus/shrimp)

Dose et al., 2016, [97]

β-carotene

Radical-trapping (in carrot)

Palozza & Krinsky, 1992 [98]

Colostrinin

GSH regulation (bovine colostrum)       

Boldogh & Kruzel, 2008 [99]

Curcumin

Free radical scavenger (ginger)         

Sreejayan & Rao, 1996 [100]

Ginko biloba

Flavnoids-free radical scavenger (ginko leaf) 

Qiu et al., 2017 [101]

Indole-3-carbinol (I3C)

Free radical scavenger (cruciferous)

Arnao et al., 1996 [102]

Idebenone

Free radical scavenger (synthesized)

Mordente et al., 1998 [103]

Isoflavones

Free radical scavenger (Soy bean)

Rimbach et al., 2003 [104]

Lutein

Free radical scavenger (green leafy vegetable)

Sies et al., 1992 [105]

Lycopene

Free radical scavenger (tomato species)

Prasad & Mishra, 2014 [106]

α-Lipoic acid

 Free radical scavenger (vegetables & meat)

Petersen Shay et al., 2008 [107]

Polyphenols

Free radical scavenger (in green tea)

Yang et al., 2016 [108]

Quercetin

Free radical scavenger (vegetables & fruits)

Viturro et al., 1999 [109]

Resveratrol

Free radical scavenger (Red wine)  

Leonard et al., 2003 [110]

Selenium

Component of antioxidant enzymes (nuts)

Dodig & Cepelak, 2004 [111]

Silibinin (Sil)

Free radical scavenger (Milk thistle)

Surai, 2015 [112]

Zeaxanthin

Free radical scavenger (corn)

Sies et al., 1992 [105]

Synthesize  

N-acetylcysteine (NAC)

Dietary supplement

Portelli et al., 1976 [113] 

Table 1. Endogenous and Supplemental Antioxidants and Related Antioxidative Mechanisms

In lifetime, too many environmental factors can induce redox imbalance with over production of ROS in the mitochondria as well as other sites, named oxidative stress. Those factors include air pollutants, cigarette smoke, metal toxicity, UV radiation, pathogens attack, drug administration, hypoxia, high glucose, inflammation, depression, etc. The ROS accumulation can be resulted from over generation of ROS in various conditions, such as injury, inflammation, radiation, chemical drugs, etc. as mentioned above. Alternatively, ROS accumulation and oxidative stress (OS) could be due to the diminished abilities in the elimination of ROS. For example, reduction in the level of GSH causes redox imbalance in many disorders, such as in Parkinson’s diseases, HIV infection, liver disease, and cystic fibrosis, etc. [4,5,6]. Mitochondria is a key intracellular organelle that determines survival or death of a cell by controlling cell respiratory/providing essential energy and initiating cell death signals (such as apoptosis), respectively. Following aging, mitochondria gradually decays, shown as the intrinsic rate of proton leakage across the inner mitochondrial membrane and subsequent ROS formation [7]. Intracellular ROS accumulation can oxidize lipids, proteins, and DNA, causing membrane leakage, protein mis-folding and dysfunction, gene mutations, and mitochondria dysfunction. ROS and ROS-induced molecular damages accumulate in the body and result in age-associated diseases, such as cancer.

This review article focuses on the roles of ROS in oncogenesis, and updates researches in any possible application of antioxidants for the prevention and treatment of cancers. Although reactive nitrogen species (RNS) also exert important physiological functions and over accumulation of RNS is involved in age-associated disorders, there are less information available for using anti-RNS agents as preventive and/or therapeutic interferences, and therefore RNS are not discussed in this review article.

Tumorigenesis is a multistep process, showing unlimited cell mitosis, suppressed antigrowth signals, evading apoptosis, and sustained angiogenesis [8]. ROS can induce transformation of normal cells toward phenotypes of malignant cancer via regulation of signal transductions. Mitogen-activated protein kinase (MAPK) pathway mediates cell proliferation, and ROS activates MAPK pathways in cancer cells by oxidation of Ras, an upstream activator of extracellular-regulated kinase 1/2 (Erk 1/2), and enhance cell proliferation [9]. In fact, ROS-mediated activation of MAPK pathway can be seen before transformation of a normal cell into cancer. It is well known that smoking can cause cancers. Exposure of cultured human bronchial epithelial cells to menthol and non-menthol cigarette extracts can also activate MAPK pathway via elevation of intracellular ROS production [10]. Similarly, Phosphatidylinositol-3-Kinase and Protein Kinase B (PI3k/Akt) pathway mediates cell survival, and ROS also activate PI3k/ Akt signal in the cancer cells [9]. Adduction of 4-Hydroxyestradiol, a metabolite of estradiol, to adenine (N3) and guanine (N7) of DNA from cultured human breast epithelial cells may play an important role in malignant transformation of these cells [11]. Repeated exposures of normal human mammary epithelial MCF-10A cells to 4-Hydroxyestradiol induce ROS production, and further phosphorylation (activation) of AKT through PI3K activation, leading a malignant transformation. Those researches indicate ROS-medicated signaling changes to facilitate survival and unlimited proliferation prior to cancer formation.

ROS accumulation can cause mutations of several important genes that are involved in tumorigenesis, such as Kirsten rat sarcoma viral oncogene homolog (K-Ras), tumor protein TP53, WNT, etc. [12,13,14]. Due to a domination of these mutations in tumorigenesis after ROS induction, sole application of antioxidants may be hard to control tumor progress. Following the growth of solid tumor, the tumor cells can shift from aerobic to anaerobic metabolism to adapt to low oxygen tension or hypoxia [15,16]. The cancer cells in solid tumor experience cycles of hypoxia and re-oxygenation [17,18]. Hypoxia induces ROS production in the mitochondria, and excessive ROS stabilizes hypoxia inducible factor 1 alpha (HIF-1α) by allowing it to escape from proteasomal degradation. HIF-1α further regulates glycolysis-related genes, inhibits mitochondrial respiration, resulting in hypoxic adaption of tumor cells [9] promotes the expression of genes in pro-proliferative and pro-cell survival gene pyruvate dehydrogenase kinase 1 (PDK1) and the pro-angiogenic transcription factor vascular endothelial growth factor [19]. From this point of view, application of antioxidants may block tumor progress in a way of inhibiting its adaption to anaerobic metabolism.

Oncogenesis is a process and ROS involve in its all stages, including initiation, development and devel-oped (severe or late) stages. The role and extent ROS plays in different stages can be very different.

Smoking


Smoking population is at high risk of cancers, e.g. lung cancer, oral cancer, gastrointestinal cancer, etc. Cigarette smoke extract (CSE) increases the level of ROS, activates HIF-1 and elevates gene expression of VEGF, regulated in development and DNA damage response 1 (REDD1), matrix metalloproteinases (MMPs) and heme oxygenase 1 (HO-1) in human bronchial epithelial BEAS-2B cells and lung adenocarcinoma A549 cells. The predominant role of ROS in regulation of these hazard signals were evidenced with strongly suppressions of antioxidant N-acetylcysteine (NAC) in HIF-1α protein accumulation and mRNA expressions of VEGF, HO-1, REDD1, and matrix metalloproteinase 9 (MMP-9) in CSE-treated A549 cells [20]. Antioxidant treatments have demonstrated beneficial effect on cancer preventions in animal models. Exposure of BALB/c mice to tobacco cytokeratin-5 (CK5), and increased the expressions of mesenchymal markers Snail-1, Vimentin, and N-cadherin. ERK5 showed to play a key role in tobacco smoke-mediated epithelial-mesenchymal transition (EMT). Treatment of mice with 100 mg/kg antioxidant (-)-epigallocatechin-3-gallate (EGCG; the most abundant and active polyphenol in green tea) effectively attenuated tobacco smoke-triggered activation of ERK5 and EMT in mouse stomach [21]. In animal model of azoxymethane-treated F344 rats, administration of green tea polyphenols inhibited colorectal tumorigenesis [22]. Clinical trials demonstrated that consumption of green tea significantly reduced urinary level of 8-hydroxydeoxygnaunosine (8-OHdG) in heavy smokers [23]. In a clinical study of 39 heavy smokers and 39 non-smokers, Haematococcus astaxanthin (ASX), a potent antioxidant, prevented lipid peroxidation and stimulated the activity of the antioxidant system [24]. However, antioxidants do not always introduce beneficial effect. Two large-scale trials, named the α-Tocopherol, β-Carotene Cancer Prevention (ATBC) Study and the β-Carotene and Retinol Efficacy Trial (CARET), demonstrated that the incidence of lung cancer enhanced in former and current smokers by 18% and 28% in the ATBC Study and CARET, respectively [25,26].

Obesity


Hepatocellular carcinoma (HCC) is also an age-associated fatal disease, occurring rare before age 40, progressively with older age, and highest in the incidence around ages 70-75 [27]. HCC can be resulted from chronic hepatitis virus infection (mainly HBV and HCV) and/or fatty liver. The nonalcoholic fatty liver disease (NAFLD), characterized by an intrahepatic accumulation of lipids, is the most common liver disease. Steatosis can be elicited with many risk habits and factors, such as sedentary life style, constant high-energy intake, smoking, obesity, etc. steatosis can evolve into nonalcoholic steatohepatitis (NASH) in the presence of OS and inflammation, which leads cirrhosis and HCC, fatal diseases [28]. The HCC development from steatosis is a slow process, which may provide interference opportunities.

In rodent models, antioxidants have showed therapeutic effect on fatty liver. HBV X protein (HBx) -transgenic mice spontaneously develop HCC at age between 13 and 16 months. By 6 weeks, pathological changes occur, including microsteatosis (fatty changes). Oral administration of resveratrol at 30mg/kg/d reduced the intracellular ROS to the level in wild-type mice, and effectively regressed the histopathologic change of the HBx transgenic mice in a time-dependent manner [29]. In liver fibrosis, ROS stimulates hepatic Kupffer cells to secrete transforming growth factor β1 (TGF-β1), a key fibrogenic cytokine [30,31,32]. A treatment with antioxidant ASX inhibited the expressions of TGF-β1 and nuclear factor-κB (NF-κB, a major mediator of inflammation) [33] and attenuated transforming growth factor-beta1 (TGFβ1)-induced Smad3 phosphorylation and nuclear translocation [34].

In a human study, 17 obese individuals with NAFLD were enrolled in a short-term aerobic exercise program that consisted of 7 consecutive days of treadmill walking at ~85% of maximal heart rate for 60 minutes per day. Results showed that the short-term aerobic exercise reduced ROS production and improved hepatic lipid composition while increased polyunsaturated lipid index, insulin sensitivity, high molecular weight adiponectin and maximal oxygen consumption [35]. In a phase 3 clinical trial, Vitamin E treatment was associated with a significantly higher rate of improvement in NASH in comparison with placebo group (43% vs. 19%, P=0.001). Vitamin E and pioglitazone both reduced serum levels of alanine and aspartate aminotransferases, hepatic steatosis and lobular inflammation, but not fibrosis scores [36]. In general, antioxidant interference seems to affect steatosis and NASH, and prevent cirrhosis and HCC.

Inflammation


Under inflammation, inflammatory and epithelial cells release ROS, which are capable of causing DNA damage [37] Therefore, antioxidants should theoretically block inflammation-induced cancers, at least partly.

In mouse model of inflammation-driven lung cancer b y 4 - ( m e thylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, a key tobacco-specific nitrosamine) and lipopolysaccharide (LPS, a potent inflammatory agent), a treatment with a combination of antioxidants indole-3-carbinol (I3C) and silibinin (Sil) reduced numbers of lung tumors/mouse by 52% [38]. Moreover, the number of largest tumors (>1.0mm) was significantly reduced from 6.3±2.9 lung tumors/mouse in the control group to 1.0±1.3 and 1.6±1.8 lung tumors/mouse in mice given I3C + Sil and I3C alone, respectively. Meanwhile the level of proinflammatory and procarcinogenic proteins, such as phospho-Signal transducer and activator of transcription 3 (pSTAT3), phospho-Inhibitory Subunit of NF Kappa B Alpha (pIκBα) and cyclooxygenase 2 (COX-2), and proteins that regulate cell proliferation, exampled as pAkt, cyclin D1, cyclin-dependent kinase (CDKs) 2, 4, 6 and retinoblastoma protein (pRB), significantly reduced with I3C + Sil treatment. This demonstrated a potential lung cancer chemopreventive effect of I3C + Sil in smokers/former smokers with a progressive liver disease, as mentioned above. Sil showed antioxidant, hypoinsulinemic and hepatoprotective properties that act against NASH-induced liver damage in a rat NASH model [39]. In this study, NASH rats developed all characteristic hallmarks of the pathology. Treatment with Sil improved liver steatosis and inflammation, and decreased NASH-associated lipid peroxidation, plasma insulin level and TNF-α expression, while decreased superoxide release and lipid peroxidation. Prostaglandin E2 (PGE2) actively mediates inflammatory process, that is involved in oncogenesis. In a Phase I clinical trial with fifteen patients with advanced colorectal cancer refractory to standard chemotherapies, consumption of capsules compatible with curcumin dose of 3.6 g daily for up to 4 months engendered 62% and 57% decreased in inducible PGE2 production in blood samples taken 1 hour after dosing on days 1 and 29, respectively, of treatment compared with levels observed immediately pre-dosing [40].

Although many positive results in cancer prevention, as mentioned above, have been obtained from preclinical and clinical studies, there have been controversial evidences from clinical studies in the effect of antioxidants on the incidence of cancers. Certain studies have demonstrated very encouraging outcomes. About 30% of men with high-grade prostate intraepithelial neoplasia (HG-PIN) would develop prostate cancer within 1 year after repeated biopsy. A double-blind, placebo-controlled trial of sixty volunteers with HG-PIN was to study the effect of green tea catechin (GTC) on the incidence of prostate cancer. In treatment group, daily treatment consisted of three GTCs capsules, 200 mg each (total 600 mg/d). One year later, only one tumor was diagnosed among the 30 GTCs-treated men (incidence, approximately 3%), whereas nine cancers were found among the 30 placebo-treated men (incidence, 30%). No significant side effects or adverse effects of GTC were observed. As a secondary observation, administration of GTCs also reduced lower urinary tract symptoms, suggesting that these compounds might also be of help for treating the symptoms of benign prostate hyperplasia [41]. In separate studies, tea consumption is also reported to show negative correlation to risk of prostate cancer [42,43]. Furthermore, meta-analysis of published observational studies revealed that tea intake is associated with decreased risk of biliary tract cancer and liver cancer [44,45]. In contrast to these, some clinical studies showed no effect or even negative effect of antioxidants on the incidence of cancers. A double-blind randomized controlled trial of dietary supplements containing lycopene, selenium, and green tea catechins (important polyphenols) was carried out in men with multifocal high grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation. The result indicated that administration of high doses of lycopene, selenium, and GTCs in these high-risk populations was associated with a higher incidence of prostate cancer, shown with re-biopsy and molecular analysis [46]. Another group obtained similar result from a placebo-controlled, randomized clinical trial of polyphenon E, a proprietary mixture of green tea catechins in 97 men under the same high-risk condition [47]. In a statistical analysis of 756 incident breast cancer cases and 789 hospital controls, regular tea drinking was significantly associated with a lower risk for breast cancer in pre-menopausal women, but an increased risk in post-menopausal women [48].

In general, it seems that effective, no effective, or adverse effective an antioxidant acts may be dependent on the state of an individual, and the type and dose of the antioxidant. Therefore, application of an antioxidant should be very cautious, and of course, more precise studies are required to determination the optimal type and dose of antioxidants and individual conditions.

Cancer cells usually show higher level of intracellular ROS than normal cells, which is essential to maintain their proliferation and malignancy. The strategies for cancer therapy, therefore, would be increase of ROS level of cancer cells beyond the threshold of leading the cell to death, such as by chemotherapeutic drugs, or reduce intracellular ROS level, exampled as the cases using antioxidants.

Melatonin (N-acetyl-5-methoxytryptamine), secreted by the pineal gland, is a potent free radical scavenger with anti-oxidant properties. It can inhibit cell growth of several cancer cells, including breast cancer, ovarian cancer, leiomyosarcoma, pancreatic cancer, hepatic cancer, coloristic cancer, lung cancer, etc. [49]. Although melatonin can affect many signaling pathways, suppression of ROS can be a mechanism underpinning its function. For instance, intracellular GSH in human breast cancer MCF-7 cells steadily decreased following the cell culture duration, and melatonin at physiological concentration increased intracellular concentration of GSH and inhibited in vitro growth of human breast cancer cells by GSH-mediated pathway [50].

EGCG reduced intracellular ROS in normal cells, and protected hepatocytotoxicity of anticancer drug doxorubicin [51], nephrotoxicity of immunosuppressant FK506 [52] and neurotoxicity of an endogenous metabolite of tryptophan 3-Hydroxykynurenine [53] inhibited cell viability of cisplatin-resistant oral cancer CAR cells by inducing apoptosis and autophagy in a time- and concentration-dependent manners [54]. In contrast to ROS suppression in normal cells, EGCG seemed to inhibit growth of cancer cells via elevation of oxidative stress. EGCG inhibited proliferation of primary endometrial adenocarcinoma cells, down-regulated the expression of proliferation markers, i.e., estrogen receptor α, progesterone receptor, proliferating cell nuclear antigen and cyclin D1, and decreased the activation of ERK and downstream transcription factors fos and jun. The cancer cells died of apoptosis, shown by up-regulation of proapoptotic Bax and down-regulation of antiapoptotic protein Bcl2, which was mediated with ROS induction, evidenced by blockage of the cell death by pretreatment with the ROS scavenger NAC and reduction of GSH level by EGCG [55]. EGCG-induced cancer inhibition may be also via ROS-mediated non-apoptotic cell death since EGCG promoted production of intracellular ROS and enhanced lysosomal membrane permeabilization. Treatment with NAC reduced lysosomal membrane permeabilization and protected cell death of human cancer cells HepG2 and Hela from EGCG insult [56]. EGCG was also showed, at low dose and high dose, separately inducing apoptotic and necrotic cell death of malignant mesothelioma (MMe) cells in culture, by releasing H2O2 into cell culture and elevating intracellular free calcium and ROS [57]. Interestingly, this study showed that EGCG was selectively cytotoxic to MMe cells with respect to normal mesothelial cells. The selective death of cancer cells in response to EGCG was supported by another study, in which human telomerase reverse transcriptase (hTERT)-mediated apoptosis by EGCG-induced ROS was compared in normal cells and cancer cells. The results showed differential levels of ROS induction between the cell types - ROS, especially hydrogen peroxide, was highly induced in cancer cells, while it was not in normal cells. The preferential death of cancer cells by EGCG could be caused by the cancer-specific induction of ROS and epigenetic modulation of expression of apoptosis-related genes hTERT [58]. Similar to EGCG, soy isoflavone genistein, as an antioxidant, protected neurons from OS [59]. However, genistein also induced cell death of breast cancer cells through mobilization of endogenous copper ions and generation of reactive oxygen species. The genistein-induced apoptosis in these cells can be inhibited by ROS scavengers, implicating ROS as effector elements leading to death of breast cancer cell [60]. Obviously, cancer cells show different response of ROS regulation to the same antioxidant from normal cells. This phenomenon may help developing antioxidant as therapeutic drugs or adjuvant therapy with anticancer drugs or radiotherapy. Since radiotherapy and many of anticancer drugs exert their function in killing cancer cell by increase cellular ROS level, using antioxidant together with these therapeutic ways may interference with the efficacy of chemotherapy or radiotherapy. Therefore, a caution should be taken when an antioxidant is applied as an adjuvant agent for reduction of therapeutic side effects. ROS may play an important role in cancer metastasis, leading a cancer to clinical-defined late stage, by allowing cancer cells independent of attachment to extracellular matrix, promoting expression of MMP, inactivating MMP inhibitor -tissue inhibitor of metalloproteinase (TIMP), and increasing the vascular permeability [9]. Thus, application of antioxidants should, theoretically, be an important strategy for prevention of cancer metastasis preceded to its late and fatal stage, and may increase lifespan of a cancer patient. Renal cell carcinoma (RCC) is the most lethal of all urological malignancies because of its potent metastasis potential. Melatonin exerts multiple tumor-suppressing activities through antiproliferative, proapoptotic, and anti-angiogenic actions and has been tested in clinical trials. Melatonin at the pharmacologic concentration was found considerably reducing the migration and invasion of RCC cells (Caki-1 and Achn) in vitro and in vivo, and the mechanism underlying its roles demonstrated as transcriptional inhibition of MMP-9 by decreasing p65- and p52-DNA-binding activities [61]. Melatonin was also found reducing angiogenesis in serous papillary ovarian carcinoma of ethanol-preferring rats by downregulating TGFβ1 and VEGF [62]. Low doses of curcumin suppressed growth and migration of oral cancer [63]. Mechanistically, curcumin inhibited the cell proliferation of bladder cancer T24 and 5637 cells, and reduced the migration and invasive ability of the cancer cells via regulating β-catenin expression and reversing epithelial-mesenchymal transition [64].

However, there have been controversy results obtained for the roles of the same antioxidant in cancer metastasis. For example, antioxidant NAC inhibited in vitro cell migration of mouse melanoma cells [65] and lung metastasis in nude mice [66]. In contrast, the research demonstrated that NAC increased lymph node metastases in an endogenous mouse model of malignant melanoma but has no impact on the number and size of primary tumors. NAC and the soluble vitamin E analog Trolox markedly increased the migration and invasive properties of human malignant melanoma cells as well, but did not affect their proliferation [67]. Perhaps experimental models have big difference in determination of an antioxidant effect on cancer metastasis. The optimal model should represent a human cancer condition.

Cancer in late stage manifests dysfunction of important organs, which is elicited with cancer metastasis, infections, and perhaps damage with over chemotherapy and/or radiotherapy, etc. In this stage, reverse of life by completely removing cancer become less possible, but rarely people will give up therapy. Therefore, prevention of therapeutic side-effects will be the first priority for improvement the quality of life. In this stage, patients commonly experience severe side effects or unendurable suffers of chemotherapy, such as cognitive impairment or peripheral nerve impairment. Experimental data have demonstrated that ROS burst plays a key role in the damage of nervous systems. Radiation can result in fragmentation of lipid in a model membrane through induction of peroxidation [68].

Antimetabolite drugs, methotrexate (MTX) and 5-fluorouracil (5-FU), widely used chemotherapeutic agents, are most likely to cause the central nervous system (CNS) toxicity [69]. MTX result in an increase of ROS in cerebral spinal fluid and executive dysfunction in chemotherapeutic patients of pediatric acute lymphoblastic leukemia [70, 71]. Although there are yet no reports of 5-FU increasing ROS in CNS, it has been observed to induce apoptosis in rat cardiocytes through intracellular ROS [72], to increase ROS in the plasma of liver cancer patients [73], and to decrease GSH in bone marrow cells [74]. Our previous study showed that either 5-FU or MTX elicited in vitro neurotoxicity to primary culture of embryonic brain neurons is ROS-dependent [75]. Thus, 5-FU or MTX each has dual functions, inhibiting cancer cells by competing with DNA synthesis and eliciting neurotoxicity through induction of ROS burst. PAN -811 was originally designed as an anticancer drug, targeting ribonucleotide reductase [76], but it also showed outstanding neuroprotective efficacy with a function as a free radical scavenger [77]. PAN-811 efficiently protected cultured neurons from 5-FU or MTX insult, and manifested a synergic effect with the anticancer drug in cancer cell inhibition [75]. Furthermore, our latest results from animal study showed that PAN-811 significantly preserved cognitive function, and preserved neurogenesis in gyrus dentate under 5-FU and MTX insults (Unpublished observations). PAN-811 has dual functions of cancer suppression and neuroprotection, and thus can be a potential drug for reducing CNS side effect during chemotherapy with ROS-independent anticancer drugs, and requires further clinical studies.

Radiotherapy is commonly used to treat a number of malignant tumors. Although highly effective and now more targeted, many patients suffer side effects, such as small intestine toxicity. The symptoms include post-prandial pain, acute or intermittent small intestine obstruction, nausea, anorexia, weight loss, bloating, diarrhea, steatorrhea and malabsorption of selected or multiple nutrients, which can have a significant impact on patient’s quality of life [78]. Ionizing radiation can result in generation of ROS which often contain unpaired electrons making them highly reactive and damaging [79]. Pathologically, radiation-induced intestinal damage shown as crypt cell death, mucosal breakdown, microcirculation disorder, leukocyte cell adhesion and emigration [80,81,82]. In mice, irradiation induced architectural disorganization of intestine, including inflammatory mononuclear cell infiltration, villitis, and desquamation with eosinophilic necrosis, and diminished mucosal thickness, crypt height, and villous height. A treatment with melatonin well preserved villous pattern, mucosal thickness, crypt height of irradiated intestine [83]. Similar result was also observed for resveratrol in irradiated mouse model [84]. In addition, curcumin also protected ileal mucosa of rats from gamma radiation- induced damage [85]. In a study of 30 patients with chronic radiation enteritis or proctitis, a treatment with pentoxifylline/tocopherol showed symptomatic improvement in 71% of patients, in comparison with 33% of patients who experienced a spontaneous relief of their symptoms [86].

1. The effectiveness of antioxidants in prevention of cancer is too early to make conclusion yet. It needs fine-designed clinical trials, and perhaps precision medicine to define the recruiting subpopulations, select mitochondrial- or out-mitochondrial-targeting antioxidants, and determine dose variation and treatment durations;
2. Whether AOs can be applied for cancer therapy can be most difficult judgement. The complexity of ROS relevant pathways in different types of cancers and different states of a given cancer is obviously much beyond our present knowledge. Intensive studies are perhaps required to optimal preclinical models, study an AO for a certain cancer at a given stage, monitor AO pharmacokinetics,
3. Antioxidants may be applied for suppression of ROS- mediated side effect of ROS-independent anticancer drugs in late stage of cancer, when it has already metastasized. Application of AOs to suppress of chemo- or radio- therapy-induced side effects aims to improve the life quality.

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Citation: Jiang ZG, Ghanbari HA (2017) A Potential Application of Antioxidants in Managing Cancer Progression J Precision Med Public Health 1:005

Published: 15 October 2017

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