DNA strand breaks and hypoxia response inhibition mediate the radiosensitisation effect of nitric oxide donors on prostate cancer under varying oxygen conditions

Stewart, Grant D.; Nanda, Jyoti; Katz, Elad; Bowman, Karen J.; Christie, Jill G.; Brown, David Jg; McLaren, Duncan B.; Riddick, Antony C. P.; Ross, James A.; Jones, George D.D.; Habib, Fouad K.

doi:10.1016/j.bcp.2010.09.022

Cited by 36 publications

(18 citation statements)

References 38 publications

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“…8 Hypoxia and radiation sensitivity are particular characteristics in numerous solid human tumors that can be exploited for selective cancer therapy. 9,10 By combining the two characteristics, we previously devised a special AND gate vector by connecting the radiation-responsive promoter cArG 6 to the heat shock response signal elements SNF1, heat shock factor-1 and heat shock element ( Figure 1). This AND gate genetic circuit has been demonstrated to be activated by 6 Gy of radiation and 1% O 2 treatments together but not alone, and to regulate the therapeutic gene p53 expression in hypoxic tumor cells receiving radiation, instead of peritumoral and other hypoxic normal cells in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

The radiation dose-regulated AND gate genetic circuit, a novel targeted and real-time monitoring strategy for cancer gene therapy

Ding

Zhang

et al. 2012

Cancer Gene Ther

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The AND gate functions such that when all inputs are activated the downstream gene will be transcribed and it is off otherwise. To accomplish optimal and targeted gene therapy in solid tumor patients, we have constructed an AND gate genetic circuit and investigated whether it could be activated by low-dose radiation in vitro and in vivo. The enhancement green fluorescent protein (EGFP) expression in different tumor cells transfected with control vector plxsn-EGFP confirmed that 2 Gy of radiation and 1% O 2 for 3 h could activate our AND gate. Besides, the obvious different levels of EGFP expression between 2 and 6 Gy of radiation demonstrated that the AND gate could be regulated by radiation doses. Additionally, through EGFP expression and the codistribution of p53 and HIF-1a in xenografts, we illustrated the targeted activation property of the AND gate and real-time monitoring to hypoxic districts in vivo. Moreover, significant growth inhibition and cell cycle arrest in vitro and apoptosis-inducing effects in vitro and in vivo proved that the AND gate induced ideal antitumor effects. In conclusion, the radiation dose-regulated AND gate genetic circuit could not only effectively monitor the therapeutic process in real-time but also induce ideal antitumor efficacy, and can be further exploited for personal therapy in clinical tumor patients.

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Section: Introductionmentioning

confidence: 99%

The radiation dose-regulated AND gate genetic circuit, a novel targeted and real-time monitoring strategy for cancer gene therapy

Ding

Zhang

et al. 2012

Cancer Gene Ther

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“…3A). H2A.X is required for DNA fragmentation and is phosphorylated at Ser 139 when exposed to apoptotic stimuli [27,28]. Paclitaxel induced a dramatic increase of H2A.X phosphorylation after a 24-h treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Pim-1 knockdown potentiates paclitaxel-induced apoptosis in human hormone-refractory prostate cancers through inhibition of NHEJ DNA repair

Hsu

Leong

et al. 2012

Cancer Letters

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The knockdown of Pim-1 or inhibition of Pim-1 activity significantly increased c-H2A.X expression. The effect was correlated to apoptosis and was attributed to the inhibition of nonhomologous DNA-end-joining (NHEJ) repair activity supported by the following observations: (1) inhibition of ATM and DNA-PKcs activities, (2) down-regulation of Ku expression and nuclear localization and (3) decrease of DNA end-binding of both Ku70 and Ku80. The data suggest that Pim-1 plays a crucial role in the regula-tion of NHEJ repair. In the absence of Pim-1, the ability of DNA repair significantly decreases when exposed to paclitaxel, leading to severe DNA damage and apoptosis.

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“…NO mimetics significantly inhibit hypoxia-induced resistance to doxorubicin and 5-flourouracil in a variety of cell types [26,146]. In PC-3 prostate cancer cells, NO-Sulindac reduces the hypoxic signature by mitigating HIF-1 levels and this effect of NO results in a greater sensitivity to radiation [148,149]. Collectively, these studies reveal that NO is able to regulate an array of O 2 -sensitive phenotypes.…”

Section: No In the Mitigation Of Hypoxia-induced Phenotypesmentioning

confidence: 87%

Role of Nitric Oxide in the Regulation of the Pro-tumourigenic Hypoxic Phenotype: From Instigation to Mitigation

Postovit

2015

Nitric Oxide and Cancer: Pathogenesis and Therapy

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Low oxygen levels (hypoxia) are a biophysical consequence of tumour growth that exceeds vascular capacity. Hence, hypoxia is commonly present in solid tumours. Many studies, spanning decades, have demonstrated that the extent of tumour hypoxia is positively correlated with a poor clinical prognosis. These clinical findings have been corroborated with laboratory-based studies demonstrating that hypoxia induces hallmarks of cancer such as metabolic reprogramming, metastatic potential, immune cell evasion and angiogenesis. Accordingly, there has been a great emphasis placed on the need to understand the mechanisms by which hypoxia promotes tumourigenic phenotypes; so that interventional therapeutics can be developed. One candidate modulator of the hypoxic response is Nitric Oxide (NO). In this review, we describe how NO can mimic or mitigate the effects of hypoxia in tumours in a context and concentration-dependent manner. We further reveal emerging research suggesting that NO signalling may be harnessed to prevent tumour progression.

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DNA strand breaks and hypoxia response inhibition mediate the radiosensitisation effect of nitric oxide donors on prostate cancer under varying oxygen conditions

Cited by 36 publications

References 38 publications

The radiation dose-regulated AND gate genetic circuit, a novel targeted and real-time monitoring strategy for cancer gene therapy

The radiation dose-regulated AND gate genetic circuit, a novel targeted and real-time monitoring strategy for cancer gene therapy

Pim-1 knockdown potentiates paclitaxel-induced apoptosis in human hormone-refractory prostate cancers through inhibition of NHEJ DNA repair

Role of Nitric Oxide in the Regulation of the Pro-tumourigenic Hypoxic Phenotype: From Instigation to Mitigation

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