Cancer Letters

Cancer Letters

Volume 227, Issue 2, 28 September 2005, Pages 133-139
Cancer Letters

Carcinogenesis and Cancer Prevention
Glutathione peroxidase, glutathione-S-transferase, catalase, xanthine oxidase, Cu–Zn superoxide dismutase activities, total glutathione, nitric oxide, and malondialdehyde levels in erythrocytes of patients with small cell and non-small cell lung cancer

https://doi.org/10.1016/j.canlet.2004.12.005Get rights and content

Abstract

Lung cancer is a common pathology with high mortality due to late diagnosis. Glutathione peroxidase (GSH-Px), glutathione-S-transferase (GST), catalase (CAT), xanthine oxidase (XO), Cu–Zn superoxide dismutase (Cu–Zn SOD) activities, total glutathione (TGSH), nitric oxide (NOradical dot), and malondialdehyde (MDA) levels were investigated in erythrocytes of patients with non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), and healthy control group. We aimed to investigate serum GSH, GSH-dependent enzymes activities (GSH-Px and GST), XO, CAT, Cu–Zn SOD activity, and NOradical dot, and MDA levels in patients with NSCLC and with SCLC and correlate with the cancer stage.

Erythrocyte MDA, NOradical dot, TGSH levels and erythrocyte SOD, CAT and XO activities were significantly higher in patients with NSCLC and SCLC than in controls. Slightly increased erythrocyte GSH-Px and GST activities were not significantly different from the controls. Erythrocyte MDA level positively correlated with erythrocyte NOradical dot levels in patients with early stage (I+II) in NSCLC groups. Erythrocyte MDA level positively correlated with erythrocyte XO activity in patients with advanced stage (III+IV) in NSCLC groups. However, no other correlation could be found among the parameters in healthy controls and patients with NSCLC and with SCLC.

Results obtained in this study indicate significant changes in antioxidant defence system in NSCLC and SCLC patients, which may lead to enhanced action of oxygen radical, resulting in lipid peroxidation.

Introduction

Lung cancer is a common pathology with high mortality due to late diagnosis [1]. Cancer, a disease characterized by uncontrolled growth and spread of abnormal cells, is one of the major causes of death in humans. Carcinogenesis is generally divided into three stages: initiation, promotion and progression [2].

Several mechanisms leading to oxidative stress have been proposed in cancer patients. The first one is the altered energy metabolism, which may be attributable to symptoms such as anorexia/cachexia, nausea and vomiting. These prevent a normal nutrition and thereby a normal supply of nutrients such as glucose, proteins and vitamins, all of which lead to the accumulation of reactive oxygen species (ROS) such as hydroxyl radicals (radical dotOH), superoxide anion radical (O2·) and others [3], [4], [5]. The second mechanism is a non-specific chronic inflammation which in turn may increase ROS production [4], [5]. A third mechanism may be the result of the use of antineoplastic drugs; particularly alkylating agents and cisplatin. These are able to produce an excess of ROS and therefore lead to oxidative stress [3], [4], [5].

Cells have different antioxidant systems including low molecular weight antioxidant molecules like glutathione [6] and various antioxidant enzymes to defend themselves against free radical attacks. Superoxide dismutase (SOD), the first lines of defence against oxygen-derived free radicals, catalyses the dismutation of the superoxide anion (O2) into hydrogen peroxide (H2O2) that can be transformed into H2O and O2 by catalase. Glutathione peroxidase (GSH-Px) is a selenoprotein, which reduces lipidic or nonlipidic hydroperoxides as well as H2O2 while oxidizing glutathione. There is some evidence to suggest that the antioxidant systems allow cells to undergo normal differentiation. Alterations in the enzymatic system, in particular, are believed to play a central role in this process [7], [8], [9].

Xanthine oxidase (XO) is the last enzyme of purine catabolism. Although the enzyme participates in the oxidation of a wide variety of endogenous and exogenous substrates, it is most recognized for its role as the rate-limiting enzyme in nucleic acid degradation through which all purines are channeled for terminal oxidation. On the other hand, it catalyses conversion of xanthine and hypoxanthine to uric acid and the production of superoxide anion radical (O2·), which is potentially toxic to cellular structures [10].

Over the past decade or so, it has become evident that the free radical gas nitric oxide (NOradical dot) acts as a novel transcellular messenger molecule in many key physiological and pathological processes [11]. The role of NOradical dot in tumor biology is still poorly understood [12]. Interactions of endothelial cells of the tumor vasculature, tumor-infiltrating immune cells such as T lymphocytes and macrophages, and the tumor cells themselves regulates the growth of solid tumors. Most of these cellular components have been shown to generate NOradical dot in vitro. Endogenous NOradical dot is of a double-edged role in specialized tissues and cells, which is an essential physiological signaling molecule mediating various cell functions but also induces cytotoxic and mutagenic effects when present in excess. NOradical dot reacts rapidly with superoxide anion to form peroxynitrite, which may be cytotoxic by itself or easily decompose to the highly reactive and toxic hydroxyl radical and nitrogen dioxide (NO2·). There are actually two conflicting views on NOradical dot involvement in cancer development, considering the molecule as pro- or antitumorigenic agent [12], [13], [14].

To our knowledge, there is no available data study on erythrocyte glutathione (GSH) and GSH-dependent enzymes (glutathione peroxidase (GSH-Px), glutathione-S- transferase (GST), XO, CAT, Cu–Zn SOD activities, NOradical dot, malondialdehyde (MDA) levels in patients with non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Therefore, in the present study, we aimed to investigate serum GSH, GSH-dependent enzymes activities (GSH-Px and GST), XO, CAT, Cu–Zn SOD activity, and NOradical dot, and MDA levels in patients with NSCLC and with SCLC and correlate with the cancer stage.

Section snippets

Patients

The study protocol was approved by local ethical committee of the Medicine Faculty. The patient group included 32 (males) patients with lung cancer, and 16 healthy subjects were taken as control group (16 males), with the age range being 42–71 years (mean±SD, 59±10.1) for the patients and 42–64 years (mean±SD, 57±11.7) for the controls. The patients were classified according to TNM classification [15]: stages I (n=3), II (n=5), III (n=10), IV (n=6) for NSCLC, limited disease (n=4) or extensive

Results

The results obtained in patients and control group were summarized in Table 1. As seen from Table 1, lipid peroxidation, measured by plasma NOradical dot, erythrocyte MDA, TGSH levels and erythrocyte SOD, CAT and XO activities were significantly higher in patients with NSCLC and SCLC than in controls. Slightly increased erythrocyte GSH-Px and GST activities were not significantly different from the controls.

Erythrocyte MDA level positively correlated with erythrocyte NOradical dot levels (r=0.84, P<0.01) in patients

Discussion

Although some possible mechanisms through which oxidative stress exerts a regulatory role in tumor growth and progression including genomic instability [23], oncogene activation [24] and angiogenesis [25] are known, several important questions remain unanswered. It is not clearly known whether oxidative stress and tumor result from an increased oxidant production or from a failure of antioxidant systems [26]. Although important changes in cellular redox homeostasis during tumor growth have been

Conclusion

As a result, overall increased levels of NOradical dot, MDA, TGHS and activities of XO, CAT, CuZn SOD, and unchanged GSH-Px GST were found in patients with NSCLC and SCLC compared with the control group, which can be related to an unbalancement alteration in oxidant–antioxidant status. Although we found high NOradical dot concentrations in the patients groups, the role of NOradical dot and nitrous compounds in carcinogenesis is still under discussion. Therefore, antioxidant supplementation, which may improve antioxidant

Acknowledgements

The study was fully supported by our Faculty of Medicine.

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