Cell Proliferation and Oxidative Stress

Burdon, Roy H.; Gill, Vera; Rice‐Evans, Catherine

doi:10.3109/10715768909087937

Cited by 111 publications

(49 citation statements)

References 14 publications

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“…This supports the notion of a prooxidant tumor environment arising during tumor formation [13,14]. Yet, contrary to our hypothesis, which sought to evaluate whether a greater oxidative response correlated with a progressively enlarging tumor, we interestingly observed a greater extent of oxidation stress during the early time intervals than the 6-week time-point.…”

Section: Discussionsupporting

confidence: 63%

Oxidative status in neuroblastoma: a source of stress?

Novotny

Grosfeld

Turner

et al. 2008

Journal of Pediatric Surgery

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Aim of Study-Reactive oxygen species have been shown to be initiators/promotors of tumorigenesis. Because evidence supports the role of increased oxidative stress in solid tumors, we sought to establish this relationship in neuroblastoma (NB). The aim of the study was to investigate the extent of oxidative DNA damage and antioxidative status in a progressive animal model of human NB.Methods-Tumors were induced in the left kidneys of nude mice by the injection of cultured human NB cells (10 6 ). Blood was collected from tumor-bearing mice and controls at 2, 4, and 6 weeks. Peripheral blood leukocyte oxidative DNA damage was determined using single-cell gel electrophoresis (comet assay), and plasma antioxidant capacity was assessed by the Trolox equivalent antioxidant capacity method.Main Results-Levels of oxidative DNA damage in peripheral blood leukocytes of NB-bearing mice were increased by 166%, 110%, and 87% as compared with healthy controls at 2, 4, and 6 weeks, respectively. Plasma total antioxidant values for tumor-bearing mice were not significantly different from control mice.Conclusions-Our results indicate an increase of oxidative stress in an animal model of human NB, especially in the early stages of growth. Yet, we did not observe an appreciable response in plasma antioxidant activity. Because an altered redox status has been implicated in tumor maintenance and progression, these findings support the notion of a complex oxidant-antioxidant imbalance contributing to NB growth. By describing the oxidation status in the circulation of a well-established NB mouse model, we hope to gain insight into the host oxidative response to tumor burden. Past work evaluating tumor growth has concentrated on studying how cancer cell growth adapts and modulates to hypoxic conditions [4][5][6]. Because oxygen deficiency elevates the expression of reactive oxygen species (ROS) production, antioxidants are generated within the cell to defend against excess ROS production. By analyzing how the host responds to tumor challenge, ramifications of this work include improved understanding of the oxidative microenvironment surrounding NB growth and potentially lead to the design of new therapeutic strategies based on a child's redox status. Index words Materials and methods NB athymic mouse modelThe human NB cell line, SK-N-AS, was grown as a monolayer in Dulbecco's modified Eagle's medium with 4 mmol/L L-glutamine adjusted to contain 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, and 10% fetal bovine serum at 37°C in 5% CO 2 . Cells were harvested, counted (10 6 ), and prepared as previously described [7]. A total of 29 NCR female nude mice (4-6 weeks old) were used. After a 7-day acclimation period, mice were separated into 4 groups; group 1 (control, n = 6), group 2 (2-week tumor, n = 7), group 3 (4-week tumor, n = 7), and group 4 (6-week tumor, n = 7). Controls for each experimental group underwent a sham operation, and the left kidneys were injected (100 μL) with phosphate-buffered saline. Mice were anesthetized an...

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Section: Discussionsupporting

confidence: 63%

Oxidative status in neuroblastoma: a source of stress?

Novotny

Grosfeld

Turner

et al. 2008

Journal of Pediatric Surgery

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“…In recent years, several studies suggest metabolic production of ROS is tightly regulated and serves a physiological function during mitogenic stimulation of cultured cells (6 -11). It has been suggested that ROS operate as a key signaling process in the cascade of events leading to cell proliferation following stimulation with platelet-derived growth factor (9), epidermal growth factor (10), cytokines and antigen receptors (11), and oncogenic Ras (12). Although these studies provide evidence for a possible role of redox signaling during cellular proliferation, it is currently unknown whether antioxidant enzymes regulate progression through the cell cycle.…”

mentioning

confidence: 88%

Manganese Superoxide Dismutase Protects the Proliferative Capacity of Confluent Normal Human Fibroblasts

Sarsour

Agarwal

Pandita

et al. 2005

Journal of Biological Chemistry

111

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We tested the hypothesis that manganese superoxide dismutase (MnSOD), an antioxidant enzyme, regulates the proliferative potential of confluent human fibroblasts. Normal human skin (AG01522) and lung (WI38, CCL-75) fibroblasts kept in confluence (>95% G 0 /G 1 ) showed a significant decrease in their capacity to reenter the proliferation cycle after 40 -60 days. The inhibition of re-entry was accompanied with the agedependent increase of p16 protein levels in the confluent culture. Adenoviral mediated overexpression of MnSOD during confluent growth suppressed p16, enhanced p21 protein accumulation, and protected fibroblasts against the loss of proliferation potential. Increases in p21 protein levels in MnSOD overexpressing confluent fibroblasts were independent of p53 protein levels. p53 protein levels did not change in control, replication-defective adenovirus containing an insertless vector (AdBgl II), or AdMnSOD-infected confluent cells cultured for 20 and 60 days. In addition, MnSOD-induced protection of the proliferation capacity of confluent fibroblasts was independent of their telomerase activity. However, telomerase-transformed fibroblasts showed increased MnSOD expression in confluent growth, maintaining their capacity to re-enter the proliferation cycle. Although inactivation of the retinoblastoma protein in cells subcultured from the 60-day confluent control, AdBgl II-, and AdMnSOD-infected fibroblasts was identical, only MnSOD-overexpressing cells showed a higher percentage of S-phase. These results support the hypothesis that a redox-sensitive checkpoint regulated the progression of fibroblasts from G 0 /G 1 to S-phase.In mammalian cells, intracellular antioxidant enzymes include superoxide dismutase, catalase, and glutathione peroxidase. There are two intracellular forms of superoxide dismutase as follows: CuZnSOD, 1 found in the cytoplasm and nucleus, and MnSOD, found in mitochondria (1, 2). Different isozymes of glutathione peroxidase are found in most subcellular compartments, whereas catalase is found primarily in peroxisomes and cytoplasm (1). Antioxidant enzymes neutralize reactive oxygen species (ROS) generated from the univalent reduction of oxygen by mitochondrial electron transport chains as well as biochemical reactions of oxygen-metabolizing enzymes (3-5). ROS, including superoxide, hydrogen peroxide, hydroxyl radical, singlet molecular oxygen, and organic hydroperoxides, are oxygen-containing molecules that have higher chemical reactivity than ground state molecular oxygen. ROS have traditionally been thought of as unwanted and toxic by-products of living in an aerobic environment (6, 7). In recent years, several studies suggest metabolic production of ROS is tightly regulated and serves a physiological function during mitogenic stimulation of cultured cells (6 -11). It has been suggested that ROS operate as a key signaling process in the cascade of events leading to cell proliferation following stimulation with platelet-derived growth factor (9), epidermal growth factor (10), cytokine...

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“…(92,93), whereas higher concentrations cause a reduction in cell growth and eventually cell death. The growth promoting properties of O 2 -· at low concentrations, and cytotoxic properties at high concentrations, are illustrated in Figure 1.…”

Section: Reactive Oxygen Species As Signaling Moleculesmentioning

confidence: 99%