Oxidative stress is a state of disturbed balance between the production of reactive oxygen species (ROS) and the efficiency of antioxidants.
There are many biomarkers that are used for better understanding how oxidative stress is involved in cancer pathophysiology. This review focuses on 8-hidroxy-2-deoxyguanosine (8-OHdG) and antioxidative enzymes as biomarkers for measurement of oxidative stress in different types of cancer. This review also deals with the product of lipid peroxidation (LPO), malondialdehyde (MDA), across a variety of cancers. The use of detection of MDA levels, 8-OHdG, or antioxidant defense enzymes, has great diagnostic potential in oncology. There are studies showing that low antioxidant status and increased oxidative stress levels are detected in cancer patients, even before oncology treatment starts. Moreover, the redox status has a prognostic relevance for cancer therapy and could significantly contribute to the planning of an appropriate patient treatment regime. The conventional therapeutic strategy is based on drugs that increase ROS generation and induce apoptotic damage in cancer cells. However, this therapeutic approach has a serious disadvantage such as the development of various toxic side effects in normal tissues. It has been reported that normal cells compared to cancer cells show a low-level steady-state of ROS and constant level of reducing equivalents. The different redox status of normal and cancer cells allows the use of this parameter for the design of new promising therapeutic strategies based on the regulation of redox signaling.
Reactive oxygen species
There are endogenous and exogenous sources of ROS. ROS are highly reactive molecules that are produced by living organisms as a result of normal cellular metabolism and environmental factors and can damage nucleic acids, lipids, and proteins, thereby altering their functions. Endogenous sources of ROS are inflammatory cells, mitochondria, and peroxisomes. Inflammatory cells produce ROS by reduction of molecular oxygen. During the mitochondrial respiratory chain reaction, the biggest percentage of oxygen is metabolized to water, while up to 5% is converted to superoxide anion. It can also be produced in other processes such as in the reaction of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, xanthine oxidase, lipoxygenases, and cyclooxygenases. The organelles that produce the most of hydrogen peroxide and superoxide anions are peroxisomes. They also contain a great number of antioxidants such as catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD). Inflammatory cells, such as neutrophils, eosinophils, and macrophages produce ROS through NADPH oxidase reaction as well [Table 1].
Ionizing radiation and some environmental agents, chemical substances, alcohol, food, tobacco, chemotherapeutical agents, and infectious agents contribute to the production of ROS. Radiation is involved in all stages of carcinogenesis. It can induce apoptosis and DNA damage. Cigarettes can induce DNA lesions that lead to lung cancer, while alcohol consumption is connected to oral, head-and-neck cancer. Under physiological conditions, ROS, at lower concentrations, have positive roles in an organism such as acting as signaling molecules in cell growth cycle, migration, and differentiation of cells. When concentrations of ROS reach some critical level, apoptosis can occur. ROS are involved in the process of carcinogenesis, which includes initiation, promotion, activation of proto-oncogenes, and inactivation of stability and tumor-suppressor genes.
MECHANISMS OF CARCINOGENESIS CAUSED BY REACTIVE OXYGEN SPECIES
Continuous inflammation may lead to a preneoplastic event. In chronically inflamed cells, the secretion of a large amount of ROS/reactive nitrogen species (RNS) recruits more activated immune cells, which leads to the amplification of dysregulated processes and eventually to a preneoplastic condition. If the amount of cellular ROS/RNS produced is high enough to overcome endogenous antioxidant response, irreversible oxidative damage to nucleic acids, lipids, and proteins may cause genetic and/or epigenetic alterations leading to the dysregulation of oncogenes and tumor suppressor genes. The oxidative stress and chronic inflammation processes are tightly coupled and the failure to block these processes could result in genetic/epigenetic changes that drive the initiation of carcinogenesis. Several studies have shown that oxidative stress affects several signaling pathways associated with cell proliferation. Among them, the epidermal growth factor receptor signaling pathway can be mentioned, and key signaling proteins, such as the nuclear factor erythroid 2-related factor 2, RAS/RAF, the mitogen-activated protein kinases ERK1/2, and MEK, phosphatidylinositol 3-kinase, phospholipase C, and protein kinase C are affected by oxidative stress. Moreover, ROS alter the expression of the p53 suppressor gene that is a key factor in apoptosis. Thus, oxidative stress causes changes in gene expression, cell proliferation, and apoptosis and plays a significant role in tumor initiation and progression. Furthermore, it was revealed that ROS are causing hypomethylation of long interspersed nuclear element-1 (LINE-1) in bladder cancer cells suggesting that LINE-1 and oxidative stress have the oncogenic potential to drive tumorigenesis and cancer progression. In addition, expression of LINE-A-encoded protein (ORF1p) was experimentally induced by ROS (H2O2) in bladder cancer cells.
Reactive oxygen species damage to proteins, DNA, and lipids
Proteins are mainly functional biomolecules that drive cellular activity. Oxidative damage to proteins may result in protein dysfunction. ROS radical that induces most damage to DNA is hydroxyl radical. DNA damage plays significant roles in mutations, genetic instability, and epigenetic changes. Many kinds of oncogenes and tumor suppressor genes can suffer damage by oxidative stress causing mutations which are known to induce cancer. Most studied DNA lesion is 8-OHdG. It is mutagenic, and many studies showed that levels of 8-OHdG is elevated in many different types of cancer. 8-OHdG can pair with both adenine and cytosine, but if mismatch adenine and guanine (A: G) is not repaired there will be a transversion of regular pairs adenine and timidine (A: T), cytosine and guanine (C: G). This mutation is commonly found in oncogenes and tumor suppressor genes. 8-OHdG is used as a biomarker for evaluation of oxidative stress.
Hydroxyl (HO•) and hydroperoxyl (HO•2) radical are the most common ROS that can affect lipids. Oxidative damage to lipids causes LPO, which mainly localize in the cellular membrane resulting in a loss of membrane property. Their reactive end products can consequently damage other molecules. When exposed to low LPO, cell defense mechanisms lead to adaption, while a higher rate of LPO induces apoptosis or necrosis. Among many different aldehydes which can be formed as secondary products during LPO, MDA has been most extensively studied.
Endogenous and exogenous antioxidants can prevent and repair damage caused by ROS. Therefore, they are called “free radical scavengers” and can improve the immune defense and lower the risk of disease and cancer. Enzymatic antioxidants, which include SOD, GPx, and CAT, act by chelating superoxide and other peroxides. They act as endogenous antioxidant defense systems, which clear ROS activity and accumulation in cells and maintain redox balance. The first line of defense against free radicals is SOD, which catalyzes the dismutation of superoxide anion radical(O2 •-) into hydrogen peroxide (H2O2).
The formed oxidant H2O2 is then transformed into water and oxygen (O2) by CAT or GPx. The selenoprotein GPx enzyme removes H2O2 by using it to oxidize reduced glutathione (GSH) into oxidized glutathione (GSSG). Glutathione reductase regenerates GSH from GSSG, with NADPH. Besides hydrogen peroxide, GPx also reduces lipid or nonlipid hydroperoxides while oxidizing glutathione (GSH). In addition, nonenzymatic antioxidants (Vitamins E and C, coenzyme Q, carotene, and glutathione) serve as an important biological defense from ROS attack.
Malondialdehyde in different types of cancers
Etiology of breast cancer is connected to oxidative stress and LPO. MDA as an index of LPO was the subject of many studies. Five studies suggested an increase in MDA levels in patients with breast cancer compared to healthy controls linking the higher MDA level to over production of ROS and deficiency of antioxidant defenses. Activity of SOD was also the subject in 3 of the 4 studies mentioned above. One revealed higher activity while in other 2 lower activity was recorded.
Overexpression of SOD may be compensatory mechanism to protect from oxidative stress. On the other hand, results of lower SOD activity suggest a higher consumption of antioxidative enzymes due to oxidative stress. The levels of LPO were raised significantly from stage III to stage IV breast cancer patients. Gupta et al. have also noted that there was a significant decrease in total antioxidant capacity (TAC) compared to healthy controls. GPx and SOD activities decreased in serum samples of breast cancer patients in comparison to healthy controls. Significant finding of Pande et al. was that a level of MDA relate to a clinical stage of cancer. Level of MDA increased at higher clinical stages. Evaluation of MDA in lung cancer patients showed significantly higher excretion rate in patients then in controls. It also increased progressively with the advancement of disease, especially through stages III and IV. SOD and GPx activities were significantly decreased in the lung cancer patients compared to the controls. Similarly, reduction in activities was even more noticeable with the increase of disease stage. Furthermore, negative correlation of MDA with SOD and GPx was obtained.
Level of MDA was increased in prostate cancer patients, compared to healthy controls and patients with benign prostate hyperplasia. Dillioglugil et al. also correlated current prognostic indicators for localized prostate cancer with MDA, which showed strong relationship between all known prognostic indicators of prostate cancer and MDA levels. DNA damage was proven with an increase in excreted 8-OHdG in urine. They concluded that DNA damage levels lead to an increase in oxidative damage and may consequently play an important role in prostate carcinogenesis.
Concerning renal and bladder cancer, serum MDA levels was significantly higher in both types of cancer, but with no correlation with a stage of the disease. Other study showed that serum MDA levels were significantly higher in bladder cancer patients and progressively increasing with severity of the disease, indicating its role in tumor development and growth. In addition to this, TAS levels in bladder cancer patients were shown to be significantly lower than in controls.
Levels of LPO and antioxidant status were also measured in patients with oral cavity and oropharyngeal cancer. Levels of MDA were higher, while levels of plasma antioxidants were lower in oral cavity and oropharyngeal cancer patients than healthy controls.
Surprisingly, there are studies which showed that MDA was significantly lower in the gastric cancer and colorectal patients compared to those of controls, while DNA damage expressed through values of 8-OHdG, was higher in patients as expected. It is proposed that the decreased levels of MDA, may relate to tumor aggressiveness, in a way that rapidly dividing cells tend to set an oxidant-antioxidant status favorable to their growth. Rapidly proliferating tumor cells show resistance to LPO and overexpress antioxidant enzymes. On the other hand, several studies showed increased levels of MDA, one suggesting that the combination of MDA and carcinoembryonic antigen, as a standard prognostic marker, provide higher diagnostic accuracy, then when used alone.
A significant increase of MDA in colorectal cancer was shown, together with a decrease in antioxidants (Vitamin E and Vitamin C), suggesting that higher oxidative stress level and lower antioxidative defense level, play important role in tumor progression and pathogenesis. In addition, LPO was increased in groups with different stages of colorectal cancer compared to the control, but without significant differences between groups.
LPO levels were also significantly higher in liver cancer patients compared to healthy controls. Antioxidant enzymes SOD and CAT, as well as exogenous antioxidants, were significantly lower in patients.
Higher levels of MDA and lower levels of SOD, CAT, vitamin C and E were observed in ovarian cancer patients compared to healthy controls. The low levels of antioxidants and increased levels of LPO is due to increased levels of oxidative stress in ovarian cancer patients, which is believed to be due to excessive ovulation or epithelial inflammation. In addition, the levels of oxidative stress were found to be higher in stage IV ovarian cancer patients than patients in stage II. Level of lipid peroxides was also significantly higher in stage II and above in cervical carcinoma than that of healthy individuals.
8-hidroxy-2-deoxyguanosine in different types of cancer
Statistically significant higher values of 8-OHdG were shown in gastric cancer patients. 8-OHdG was measured in patients with chronic atrophic gastritis (CAG) and gastric carcinoma (GC) and compared with controls. It was higher in both patient groups (CAG and GC) then in controls. In addition, MnSOD was expressed to a greater extent in GC group, when compared to control. It is advised that CAG patients who express 8-OHdG and MnSOD highly should be monitored for the potential occurrence of GC.
In one study, 8-OHdG was suggested to be a prognostic factor in epithelial ovarian carcinoma. High levels of 8-OHdG were associated with a poor ovarian cancer-specific survival, correlating with the traditional factors of poor prognosis and serous histology.
The serum 8-OHdG concentrations were also noticeably higher in Stage III–IV carcinomas compared with more localized ovarian tumors. Increased 8-OHdG level was found in high-grade papillary serous carcinomas but neither low-grade papillary serous carcinomas nor cystadenoma, indicating poorer overall, and progression-free survival.
Colorectal cancer is associated with oxidative stress, and assessment of oxidative stress and antioxidants is important for the treatment and prevention of colorectal cancer.
One study reported higher levels of 8-OHdG in patients group then in control one, while the activity of antioxidative enzymes was significantly decreased. On the other hand, level of 8-OHdG and activity of GPx were found to be decreased, and SOD activity increased in both gastric and colon cancer groups compared to control one. In addition, SOD activity was positively correlated with cancer antigen 15-3 (CA-15-3, standard marker for prognosis in the gastric cancer group). Low plasma level of 8-OHdG and altered antioxidant activity may implicate the deficient repair of oxidative DNA damage in patients with gastric and colon cancer.
Mean level of 8-OHdG in three groups of patients with colorectal carcinoma (adenoma, early cancer, and advanced cancer) was measured. Level of 8-OHdG was significantly increased in adenoma and early cancer, proposing them as a risk factor for colorectal adenoma and early cancer. 8-OHdG was not detected at high level in patients with advanced cancer, possible due to decreased energy intake and nutritional disorders in patients with advanced cancer.
Redox imbalance was observed in head-and-neck carcinoma patients. Rise in ROS as well as 8-OHdG levels, accompanied by significant lowering in TAC and GSH showed its importance in the development of the head-and-neck carcinoma.
One study investigated 8-OHdG as indicator of oxidative stress in esophageal cancer. The 8-OHdG level was higher in cancerous areas than in normal epithelia.
Antioxidative enzymes in different types of cancer
Activities of CAT and SOD have shown a remarkable reduction in cervical neoplastic tissue in stages II, III, and IV, while GPx and GR were significantly lower in stage III and IV patients in comparison to healthy controls. The activity of glutathione-S-transferase was significantly higher in stage II, III, and IV and above than that of normals, implicating impaired antioxidant status in carcinoma of the uterine cervix.
Blood levels of SOD and GPx, and serum TAC was significantly lower with advancing stage of bladder cancer.
Antioxidant defense mechanism (SOD, CAT, GST, and GPx) was weakened, and enhanced free radical activity has been shown in breast cancer patients.
Mn-SOD content and its immunohistochemical localization in human thyroid tumors and some other thyroid diseases were examined and compared with adjacent normal thyroid tissue. The content of Mn-SOD was increased in diffusehyperplasia, adenomatous goiter, and follicular adenoma. In papillary carcinoma, it was significantly higher than in adjacent normal thyroid tissue. Follicular carcinoma also revealed a markedly high Mn-SOD content. In the immunohistochemical study, adjacent normal thyroid tissue showed granular positive staining of Mn-SOD in the cytoplasm. An increase of Mn-SOD was observed in the papillary proliferative lesion of diffuse hyperplasia and in the follicles adjacent to lymphoid tissue in chronic thyroiditis with hypothyroidism. Strong positive staining of Mn-SOD was observed in papillary and follicular carcinomas, whereas in anaplastic carcinoma staining was markedly less intense. These results indicate that the Mn-SOD content varies according to the degree of differentiation of thyroid carcinomas.
Superoxide anion scavenger, MnSOD, is not readily detected in normal brain tissue. It is however markedly expressed in malignant central nervous system tumors, including tumors metastatic to the brain. In Grade II astrocytomas, it was less expressed than in Grade IV astrocytomas (glioblastomas), Grade III astrocytomas, and medulloblastomas and up to 45 times more than the level found in controls. MnSOD is increasing is in a direct relationship with tumor grade in brain tumor tissues.
Enhanced expression of Mn-SOD and lower expression of copper/zinc SOD compared with their corresponding normal mucosa was found in gastric malignant tissues. In particular, the Mn-SOD ratio (levels in normal and malignant tissue) is revealed as an independent prognostic parameter in gastric cancer patients, and it seems to be clinically relevant for patients survival (the higher the ratio, poorer overall survival). A study that compared gastric cancer patients with and without metastases, MnSOD was upregulated in the primary tumors with lymph node metastases, supporting involvement of MnSOD and possibly ROS in metastasis.
In ovarian cancer tissues, a significantly higher level of Mn-SOD expression was observed compared to normal tissues. When Mn-SOD expression was suppressed, a 70% increase of superoxide in ovarian cancer cells was noted, which lead to stimulation of cell proliferation in vitro and more aggressive tumor growth in vivo.
Protein levels and activity of SOD were significantly decreased in colorectal carcinomas. CuZn-SOD protein levels, but not Mn-SOD levels or total SOD activity were related with differentiation grade and to a lesser extent with the Dukes stage. Moderately differentiated carcinomas and the Dukes stage A carcinomas showed lowest levels. Some carcinomas expressed elevated levels of CuZn-SOD, and this was an indication of poor survival. It is concluded that decreased SOD expression is not a prognostic marker and seems to be a secondary phenomenon rather than directly linked with the carcinogenetic process. SOD activity was lower in all colorectal carcinoma groups than in controls. In addition, a significant increase in SOD activity was shown in tumor stage IV when compared with stage II. On the contrary, CAT and GPx activities show no significant differences between colorectal carcinoma groups, but generally it was increased when compared to the control. The activity of glutathione reductase, on the hand, is lower in all colorectal carcinoma groups and a significant decrease has been shown between patients in tumor stage II and III compared to tumor stage IV leading to the conclusion that progression of the disease is followed by an increase in redox disbalance.
CAT activity is significantly lower in patients with lung cancer compared to controls. Those levels were even more decreased in patients with metastasis.
SOD and CAT activity decreased in chronic lymphocytic leukemia (CLL) lymphocytes while GPx activity increased. The observed changes in enzyme activities were significantly enhanced with the longevity of the disease, which points toward the role of the examined parameters as markers of the disease evolution.
In general, further caution should be addressed to dual role of ROS level in cancer cells. Prooxidant mechanisms associated with different cellular ROS levels: high levels could induce DNA damage and cell death, whereas low levels could induce epigenetic alterations and senescence-like growth arrest. ROS have a well-defined role in promoting and maintaining tumorigenicity, while on the other hand, high levels of ROS can also be toxic to neoplastic cells and can potentially induce cell death. Data from different pathological conditions, cells types, and models show a very heterogeneous picture of how ROS influence the immune system and autoimmune and inflammatory diseases. In early stages of disease development, ROS might have a beneficial impact on the prevention of autoimmune diseases, by lowering responsiveness of adaptive immune cells and/or degradation of inflammatory mediators. In contrast, the high ROS levels often observed in chronic stages of inflammation, causes cell and tissue damage and might directly or indirectly perpetuate the progression of the disease. So having in mind that higher level of ROS in cancer cells may contribute to the biochemical and molecular changes necessary for tumor initiation, promotion, progression, and chemoresistance. Escalating this higher level of ROS further to a toxic level may be beneficial for cancer treatment by enhancing chemosensitization and activation of various cell-death pathways. This model provides a rational for the development of two different contradicting anticancer therapeutic approaches having both a tumor-promoting and a tumor suppressing functions. The puzzling duality of ROS in helping or hindering the tumor progression is unavoidable. Both ROS-inducing and ROS-inhibiting strategies show complicated advantages and disadvantages. Therefore, it is critical and necessary to carefully control the amount of ROS and to deliver them directly into the tumor.
Antioxidant phytochemicals in the prevention, formation and treatment of cancer
Beneficial effects of natural polyphenols are due to their ability to scavenge endogenously generated free radicals or formed by radiation and xenobiotics. Some data suggest that the antioxidant properties of the phenolic compounds may also behave as prooxidants to initiate a ROS mediated cellular DNA breakage and consequent cell death. It has been reported that such a prooxidant mechanism is a result of redox-active microenvironment in cancer cells due to elevated levels in copper, since it is an important redox-active metal ion present in chromatin, closely associated with DNA bases and can be mobilized by metal chelating agents. The beneficial effects of polyphenols in cancer treatment can be linked to their ability to modulate, in a reversible manner, epigenetic mechanisms involved in tumorigenesis leading to gene expression activation or silencing. Many polyphenols are reported to regulate nuclear factor kappa B (NF-κB) expression and chromatin remodeling.
Natural polyphenols could induce apoptotic cell death in preneoplastic or neoplastic cells through various growth inhibitory mechanisms as the activation of cytochrome c and caspases, the arrest of cell cycle, and the modulation of signaling pathways (NF-κB, JAK/STAT) which result in the inhibition of tumor progression. Furthermore, epigenetic alterations, such as DNA methylation, histone acetylation level, and gene expression miRNA-regulated cancer stem cells biology, and induction of premature senescence in tumor cells have been identified as relevant anticancer features of many dietary polyphenolic compounds.
Prosenescence-polyphenols treatment may minimize toxicity and side effects of conventional therapies in cancer patients. On the other hand, caution in the clinical management of this therapy because the induction of senescence might give rise to quiescent tumor cells, mainly cancer stem cells, which represent a potential niche for cancer recurrence.
Assessment of oxidative stress and augmentation of the antioxidant defense system may be important for the treatment and prevention of carcinogenesis. The major goal of the present paper was to study whether levels of 8-OHdG, MDA, and antioxidative enzymes (SOD, CAT, GPx, GR) increase or decrease in different types of cancer. Furthermore, several studies focused on correlation of their levels with tumor progression. To address this aim, meta-analysis of studies of breast, prostate, lung, colon, cervical, ovarian, brain, bladder, renal, thyroid cancer, and CLL has been conducted. In general, levels of antioxidative enzymes are mostly lower in cancer patients, while 8-OHdG and MDA are higher. Further research is needed, with focus on correlation levels of these biomarkers and advancement of the disease.
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