Is there a common mechanism underlying genomic instability, bystander effects and other nontargeted effects of exposure to ionizing radiation?

Morgan, William F.

doi:10.1038/sj.onc.1206992

Cited by 189 publications

(92 citation statements)

References 33 publications

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“…Whereas IR is an effective treatment for malignant tumor cells by directly causing DNA damage (27,28), radioadaptive resistance, a specific prosurvival signaling network or radioprotective mechanisms activated by IR, has also been reported (21,29). The term radioadaptive response was originally used to describe a reduced cell sensitivity to a higher challenge dose when a smaller inducing radiation dose had been applied earlier (30).…”

Section: Discussionmentioning

confidence: 99%

Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

Koto

Murata

Kimura

et al. 2012

International Journal of Oncology

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Abstract. Zoledronic acid (ZOL), a third-generation bisphosphonate, inhibits bone resorption, as well as exhibiting direct antitumor activity. To date, however, the combined effects of ZOL and ionizing radiation (IR) have not been assessed in patients with soft tissue sarcoma. We have, therefore, assessed the combined effects of ZOL and IR in fibrosarcoma cells. HT1080 fibrosarcoma cells were treated with ZOL and/or IR, together or sequentially and the antitumor effects were assessed. We found that ZOL significantly enhanced IR-induced apoptosis, especially when cells were treated with ZOL followed by IR. We, therefore, assessed the detailed mechanism of sequential treatment with ZOL and IR. Cells in G2 and M phases, the most radiosensitive phases of the cell cycle, were not increased by low concentrations of ZOL. However, the levels of expression of Akt, ERK1/2 and NF-κB proteins, all of which are related to radioadaptive resistance, were increased within a short time after irradiation with 3 Gy, and this expression was inhibited by a low concentration of ZOL, which blocked the prenylation of small GTPases. This sequential treatment also increased the generation of reactive oxygen species (ROS). These results suggest that the combination of ZOL with IR may be beneficial in treating patients with soft tissue sarcoma.

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Section: Discussionmentioning

confidence: 99%

Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

Koto

Murata

Kimura

et al. 2012

International Journal of Oncology

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“…Moreover, because predominately low biologically/environmentally relevant doses of radiation elicit a bystander response (Nagasawa and Little, 1992;Seymour and Mothersill, 2000;Morgan, 2003), increased knowledge about this phenomenon holds important implications for individual radiosensitivity and susceptibility to radiation carcinogenesis caused by inadequate DNA repair capacity, a condition relevant to human populations and health.…”

Section: Discussionmentioning

confidence: 99%

DNA-PKcs and ATM influence generation of ionizing radiation-induced bystander signals

et al. 2008

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The phenomenon by which irradiated cells influence nonirradiated neighboring cells, referred to as the bystander effect (BSE), is not well understood in terms of the underlying pathways involved. We sought to enlighten connections between DNA damage repair and the BSE. Utilizing sister chromatid exchange (SCE) frequencies as a marker of the BSE, we performed cell transfer strategies that enabled us to distinguish between generation versus reception of a bystander signal. We find that DNAdependent Protein Kinase catalytic subunit (DNA-PKcs) and Ataxia Telangectasia Mutated (ATM) are necessary for the generation of such a bystander signal in normal human cells following gamma (c)-ray exposure, but are not required for its reception. Importantly, we also show that directly irradiated human cells do not respond to receipt of a bystander signal, helping to explain why the BSE is a low-dose phenomenon. These studies provide the first evidence for a role of the DNA damage response proteins DNA-PKcs and ATM specifically in the generation of a bystander signal and intercellular signaling.

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“…Recently, bystander responses, where cells respond to their neighbours being irradiated, have been described and are being extensively studied (see Morgan, 2003 for a review). They have been observed for a range of end points, including cell killing and therefore offer a new potential therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

ATR-dependent radiation-induced γH2AX foci in bystander primary human astrocytes and glioma cells

et al. 2006

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Is there a common mechanism underlying genomic instability, bystander effects and other nontargeted effects of exposure to ionizing radiation?

Cited by 189 publications

References 33 publications

Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

DNA-PKcs and ATM influence generation of ionizing radiation-induced bystander signals

ATR-dependent radiation-induced γH2AX foci in bystander primary human astrocytes and glioma cells

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