DNA damage, superoxide, and mutant K-ras in human lung adenocarcinoma cells

Romanowska, Małgorzata; Maciąg, Anna; Smith, Andrew L.; Fields, Janet R.; Fornwald, Laura W.; Kikawa, Keith D.; Kasprzak, Kazimierz S.; Anderson, Lucy M.

doi:10.1016/j.freeradbiomed.2007.07.004

Cited by 24 publications

(23 citation statements)

References 44 publications

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“…We noted previously in the NSCLC cell line panel a correlation between DNA strand break damage as assessed by the comet assay and the levels of superoxide. Baseline levels of total superoxide were low in H1703 cells compared with other lines, as indicated by the nitroblue tetrazolium assay (Romanowska et al, 2007). Correspondingly, the increase in mitochondrial superoxide in H1703 cells after JS-K treatment ( Fig.…”

Section: Nitric Oxide Prodrug Js-k Kills Lung Cancer Cells 317mentioning

confidence: 67%

“…Western blot analysis was performed as described previously (Romanowska et al, 2007). Primary antibodies for caspase 3, caspase 7, PARP, cleaved PARP, Bax, cytochrome c (Cell Signaling Technology, Danvers, MA), PRX 1 to 6 (LabFrontier, Seoul, Korea), and nitrotyrosine and MnSOD (Millipore Corporation, Billerica, MA) were used.…”

Section: Methodsmentioning

confidence: 99%

“…3A). IC 50 values did not correlate significantly with total levels of superoxide as measured by nitroblue tetrazolium reduction (Romanowska et al, 2007) (Supplementary Fig. S1).…”

Section: Js-k Effectiveness In Inhibiting Lungmentioning

confidence: 95%

“…We sought to determine the reasons behind the differences in sensitivity to JS-K between the cell lines. Information is available regarding the origin and cancer genes mutational status of some of the cell lines used (Phelps et al, 1996;Romanowska et al, 2007) (Table 1). There was no obvious association between JS-K toxicity and mutational status of p53 or K-ras.…”

Section: Js-k Effectiveness In Inhibiting Lungmentioning

confidence: 99%

“…There was no obvious association between JS-K toxicity and mutational status of p53 or K-ras. The cell lines had previously been characterized by us with regard to levels of ROS (Romanowska et al, 2007). Inspection of the assembled data suggested that JS-K was most effective against cell lines characterized by high levels of ROS, as detected by the oxidation-sensitive fluorophore DCF.…”

Section: Js-k Effectiveness In Inhibiting Lungmentioning

confidence: 99%

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The Nitric Oxide Prodrug JS-K Is Effective against Non–Small-Cell Lung Cancer Cells In Vitro and In Vivo: Involvement of Reactive Oxygen Species

Maciąg

Chakrapani

Saavedra³

et al. 2010

J Pharmacol Exp Ther

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Non-small-cell lung cancer is among the most common and deadly forms of human malignancies. Early detection is unusual, and there are no curative therapies in most cases. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Here, we show thatis a potent cytotoxic agent against a subset of human non-small-cell lung cancer cell lines both in vitro and as xenografts in mice. JS-K treatment led to 75% reduction in the growth of H1703 lung adenocarcinoma cells in vivo. Differences in sensitivity to JS-K in different lung cancer cell lines seem to be related to their endogenous levels of reactive oxygen species (ROS)/reactive nitrogen species (RNS). Other related factors, levels of peroxiredoxin 1 (PRX1) and 8-oxo-deoxyguanosine glycosylase (OGG1), also correlated with drug sensitivity. Treatment of the lung adenocarcinoma cells with JS-K resulted in oxidative/nitrosative stress in cells with high basal levels of ROS/RNS, which, combined with the arylating properties of the compound, was reflected in glutathione depletion and alteration in cellular redox potential, mitochondrial membrane permeabilization, and cytochrome c release. Inactivation of manganese superoxide dismutase by nitration was associated with increased superoxide and significant DNA damage. Apoptosis followed these events. Taken together, the data suggest that diazeniumdiolate-based NO-releasing prodrugs may have application as a personalized therapy for lung cancers characterized by high levels of ROS/ RNS. PRX1 and OGG1 proteins, which can be easily measured, could function as biomarkers for identifying tumors sensitive to the therapy.

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Section: Nitric Oxide Prodrug Js-k Kills Lung Cancer Cells 317mentioning

confidence: 67%

Section: Methodsmentioning

confidence: 99%

“…3A). IC 50 values did not correlate significantly with total levels of superoxide as measured by nitroblue tetrazolium reduction (Romanowska et al, 2007) (Supplementary Fig. S1).…”

Section: Js-k Effectiveness In Inhibiting Lungmentioning

confidence: 95%

Section: Js-k Effectiveness In Inhibiting Lungmentioning

confidence: 99%

Section: Js-k Effectiveness In Inhibiting Lungmentioning

confidence: 99%

See 3 more Smart Citations

The Nitric Oxide Prodrug JS-K Is Effective against Non–Small-Cell Lung Cancer Cells In Vitro and In Vivo: Involvement of Reactive Oxygen Species

Maciąg

Chakrapani

Saavedra³

et al. 2010

J Pharmacol Exp Ther

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Regulation of pancreatic cancer growth by superoxide

Nelson

Simons

et al. 2012

Molecular Carcinogenesis

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K-ras mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in the molecular pathogenesis. Expression of K-ras oncogene in an immortalized human pancreatic ductal epithelial cell line, originally derived from normal pancreas (H6c7), induced the formation of carcinoma in mice. We hypothesized that K-ras oncogene correlates with increased non-mitochondrial-generated superoxide (O2·−), which could be involved in regulating cell growth contributing to tumor progression. In the H6c7 cell line and its derivatives, H6c7er-Kras+ (H6c7 cells expressing K-ras oncogene), and H6c7eR-KrasT (tumorigenic H6c7 cells expressing K-ras oncogene), there was an increase in hydroethidine fluorescence in cell lines that express K-ras. Western blots and activity assays for the antioxidant enzymes that detoxify O2·− were similar in these cell lines suggesting that the increase in hydroethidine fluorescence was not due to decreased antioxidant capacity. To determine a possible non-mitochondrial source of the increased levels of O2·−, Western analysis demonstrated the absence of NADPH oxidase-2 (NOX2) in H6c7 cells but present in the H6c7 cell lines expressing K-ras and other pancreatic cancer cell lines. Inhibition of NOX2 decreased hydroethidine fluorescence and clonogenic survival. Furthermore, in the cell lines with the K-ras oncogene, overexpression of superoxide dismutases, that detoxify non-mitochondrial sources of O2·−, and treatment with the small molecule O2·− scavenger Tempol, also decreased hydroethidine fluorescence, inhibited clonogenic survival and inhibited growth of tumor xenografts. Thus, O2·− produced by NOX2 in pancreatic cancer cells with K-ras, may regulate pancreatic cancer cell growth.

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Oxidative damage and OGG1 expression induced by a combined effect of titanium dioxide nanoparticles and lead acetate in human hepatocytes

Zhu

Fan

et al. 2011

Environmental Toxicology

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Titanium dioxide (TiO(2)) is a widely used nanomaterial that can cause biological damage through oxidative stress. At low concentrations, TiO(2) can interact with lead acetate (PbAc) to produce different toxic responses, compared with TiO(2) or PbAc alone. In this study, we utilized the following as indicators of toxic responses in human embryo hepatocytes (L02): reactive oxygen species (ROS), reduced glutathione (GSH), superoxide dismutase (SOD), and the DNA adducts 8-hydroxydeoxyguanosine (8-OHdG) and 8-oxoguanine DNA glycosylase homolog 1 (OGG1). These were used to evaluate the oxidative stress of TiO(2) (at 0.001, 0.01, 0.1, 1, and 10 μg mL(-1)) mixed with PbAc (1 μg mL(-1)) on L02 cells without photoactivation. Compared with the negative control (1‰ dimethyl sulfoxide), TiO(2) mixed with PbAc induced increased release of ROS (at 0.001, 0.01, 0.1, 1, 10 μg mL(-1) TiO(2)), intracellular SOD activity (at 0.1 and 0.01 μg mL(-1) TiO(2)), GSH levels (at 0.01-1 μg mL(-1) TiO(2)), 8-OHdG levels (at 1 and 10 μg mL(-1) TiO(2)), OGG1 expression (at 0.001-1 μg mL(-1) TiO(2)), and cytotoxicity (at 0.1, 1, and 10 μg mL(-1) TiO(2)) in L02 cells. There were no significant changes in ROS, GSH, SOD, 8-OHdG, or OGG1 levels when L02 cells were treated with TiO(2) alone or PbAc alone. These findings indicate that TiO(2) and PbAc in combination induce cytotoxicity and oxidative stress in L02 cells in the absence of photoactivation.

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DNA damage, superoxide, and mutant K-ras in human lung adenocarcinoma cells

Cited by 24 publications

References 44 publications

The Nitric Oxide Prodrug JS-K Is Effective against Non–Small-Cell Lung Cancer Cells In Vitro and In Vivo: Involvement of Reactive Oxygen Species

The Nitric Oxide Prodrug JS-K Is Effective against Non–Small-Cell Lung Cancer Cells In Vitro and In Vivo: Involvement of Reactive Oxygen Species

Regulation of pancreatic cancer growth by superoxide

Oxidative damage and OGG1 expression induced by a combined effect of titanium dioxide nanoparticles and lead acetate in human hepatocytes

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