Chronic hypoxia modulates tumour cell radioresponse through cytokine-inducible nitric oxide synthase

Berge, Dirk L. Van den; Ridder, Mark De; Verovski, Valeri N.; Janssens, M Y; Monsaert, Christinne; Storme, Guy

doi:10.1054/bjoc.2000.1719

Cited by 20 publications

(5 citation statements)

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“…Previous in vitro investigations [6,50,51] have focused on the effects of low O 2 typical of diseases in vivo [52][53][54]. However, cells treated under these conditions were often compared to cells cultured under air, incorrectly inferring that this oxygenation was representative of "healthy" tissues, and studies have often used short-term decreases in O 2 concentration [4,5], rather than longer periods associated with disease.…”

Section: Discussionmentioning

confidence: 99%

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Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

Ferguson

Smerdon

Harries

et al. 2018

Free Radical Biology and Medicine

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In vivo, mammalian cells reside in an environment of 0.5-10% O 2 (depending on the tissue location within the body), whilst standard in vitro cell culture is carried out under room air. Little is known about the effects of this hyperoxic environment on treatment-induced oxidative stress, relative to a physiological oxygen environment. In the present study we investigated the effects of long-term culture under hyperoxia (air) on photodynamic treatment. Upon photodynamic irradiation, cells which had been cultured long-term under hyperoxia generated higher concentrations of mitochondrial reactive oxygen species, compared with cells in a physioxic (2% O 2 ) environment. However, there was no significant difference in viability between hyperoxic and physioxic cells. The expression of genes encoding key redox homeostasis proteins and the activity of key antioxidant enzymes was significantly higher after the long-term culture of hyperoxic cells compared with physioxic cells. The induction of antioxidant genes and increased antioxidant enzyme activity appear to contribute to the development of a phenotype that is resistant to oxidative stress-induced cellular damage and death when using standard cell culture conditions. The results from experiments using selective inhibitors suggested that the thioredoxin antioxidant system contributes to this phenotype. To avoid artefactual results, in vitro cellular responses should be studied in mammalian cells that have been cultured under physioxia. This investigation provides new insights into the effects of physioxic cell culture on a model of a clinically relevant photodynamic treatment and the associated cellular pathways.

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Section: Discussionmentioning

confidence: 99%

“…There is extensive literature on the effects of O 2 concentration on the efficacy of drug and radiation treatments in cancer cell killing, both in vivo and in vitro [4][5][6][7][8][9]. However, most studies have characterized these effects in vitro in cells that have been cultured, long-term, in a hyperoxic environment (i.e.…”

Section: Introductionmentioning

confidence: 99%

Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

Ferguson

Smerdon

Harries

et al. 2018

Free Radical Biology and Medicine

View full text Add to dashboard Cite

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“…EMT-6 cells have been shown to produce NO in response to various stimuli including cytokines (43), LPS (44), and chemotherapeutic drugs (45). We show here that these cells are heterogeneous with regards to NO synthesis.…”

Section: Discussionmentioning

confidence: 99%

Casein Kinase II-mediated Phosphorylation of NF-κB p65 Subunit Enhances Inducible Nitric-oxide Synthase Gene Transcription in Vivo

Chantôme

Pance

Gauthier

et al. 2004

Journal of Biological Chemistry

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“…A previous in vitro study with EMT-6 tumor cells demonstrated increased expression of iNOS following 24 hours of 1% O 2 [29] . Western blot analysis of A431 tumor lysates for iNOS showed minimal basal expression in the xenografts and no meaningful change in iNOS expression with L-NNA treatment.…”

Section: Resultsmentioning

confidence: 78%

Nitric Oxide Synthase Inhibition Enhances the Antitumor Effect of Radiation in the Treatment of Squamous Carcinoma Xenografts

Cardnell

Mikkelsen

2011

PLoS ONE

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This study tests whether the nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine (L-NNA), combines favorably with ionizing radiation (IR) in controlling squamous carcinoma tumor growth. Animals bearing FaDu and A431 xenografts were treated with L-NNA in the drinking water. IR exposure was 10 Gy for tumor growth and survival studies and 4 Gy for ex vivo clonogenic assays. Cryosections were examined immunohistochemically for markers of apoptosis and hypoxia. Blood flow was assayed by fluorescent microscopy of tissue cryosections after i.v. injection of fluorospheres. Orally administered L-NNA for 24 hrs reduces tumor blood flow by 80% (p<0.01). Within 24 hrs L-NNA treatment stopped tumor growth for at least 10 days before tumor growth again ensued. The growth arrest was in part due to increased cell killing since a combination of L-NNA and a single 4 Gy IR caused 82% tumor cell killing measured by an ex vivo clonogenic assay compared to 49% by L-NNA or 29% by IR alone. A Kaplan-Meyer analysis of animal survival revealed a distinct survival advantage for the combined treatment. Combining L-NNA and IR was also found to be at least as effective as a single i.p. dose of cisplatin plus IR. In contrast to the in vivo studies, exposure of cells to L-NNA in vitro was without effect on clonogenicity with or without IR. Western and immunochemical analysis of expression of a number of proteins involved in NO signaling indicated that L-NNA treatment enhanced arginase-2 expression and that this may represent vasculature remodeling and escape from NOS inhibition. For tumors such as head and neck squamous carcinomas that show only modest responses to inhibitors of specific angiogenic pathways, targeting NO-dependent pro-survival and angiogenic mechanisms in both tumor and supporting stromal cells may present a potential new strategy for tumor control.

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Chronic hypoxia modulates tumour cell radioresponse through cytokine-inducible nitric oxide synthase

Cited by 20 publications

References 10 publications

Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

Casein Kinase II-mediated Phosphorylation of NF-κB p65 Subunit Enhances Inducible Nitric-oxide Synthase Gene Transcription in Vivo

Nitric Oxide Synthase Inhibition Enhances the Antitumor Effect of Radiation in the Treatment of Squamous Carcinoma Xenografts

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