Mitochondrial Localization of Superoxide Dismutase is Required for Decreasing Radiation-Induced Cellular Damage

Epperly, Michael W.; Gretton, Joan; Sikora, Christine; Jefferson, Mia; Bernarding, Michael; Nie, Suhua; Greenberger, Joel S.

doi:10.1667/rr3081

Cited by 133 publications

(149 citation statements)

References 37 publications

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“…MnSOD has been described by many investigators as being an effective endogenous antioxidant enzyme capable of conferring enhanced radiation resistance to cells [4,5,8,10]. Since maximal elevation of MnSOD occurs between 16 and 24 h following exposure of cells to WR1065, it was of interest to determine whether irradiation of cells at this time would result in an enhanced cellular resistance to the cytotoxic effects of ionizing radiation.…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with the role of mitochondrial damage leading to cell death, overexpression of MnSOD in cells induced by tranfection of an MnSOD transgene gives rise to an enhanced radioresistance and to an inhibition of radiation-induced apoptosis [8][9][10]. Furthermore, it has been demonstrated that localization of superoxide dismutase within the mitochondria is a requirement for subsequent radioprotection against cellular damage [4].…”

Section: Introductionmentioning

confidence: 92%

“…The resulting survival curves were analyzed using an α/β model and compared using a Z test to determine levels of significant difference. Because MnSOD has been demonstrated to primarily affect the initial slope of the survival curve [4,9,23,24], an analysis and comparison of the α parameters of the survival curves were made. To facilitate a comparison between the various treatment conditions an α-protection enhancement ratio (αPER), defined as α control /α WR1065 , was used.…”

Section: Irradiation Conditions and Survival Assaymentioning

confidence: 99%

“…An example of such an enzyme is manganese superoxide dismutase (MnSOD). This enzyme is a nuclear-encoded mitochondrial enzyme that scavenges superoxide radicals in the mitochondrial matrix, and has been shown to be highly protective against radiation-induced reactive oxygen species (ROS) damage that can lead to cell lethality [3][4][5]. Mitochondria have been demonstrated to play an important role in the apoptotic processes induced by ionizing radiation, including the release of cytochrome c and the activation of caspase 3 that leads to PARP cleavage and subsequent DNA strand breaks [4,6,7].…”

Section: Introductionmentioning

confidence: 99%

“…This enzyme is a nuclear-encoded mitochondrial enzyme that scavenges superoxide radicals in the mitochondrial matrix, and has been shown to be highly protective against radiation-induced reactive oxygen species (ROS) damage that can lead to cell lethality [3][4][5]. Mitochondria have been demonstrated to play an important role in the apoptotic processes induced by ionizing radiation, including the release of cytochrome c and the activation of caspase 3 that leads to PARP cleavage and subsequent DNA strand breaks [4,6,7]. Consistent with the role of mitochondrial damage leading to cell death, overexpression of MnSOD in cells induced by tranfection of an MnSOD transgene gives rise to an enhanced radioresistance and to an inhibition of radiation-induced apoptosis [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

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Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

Murley

Kataoka

Weydert

et al. 2006

Free Radical Biology and Medicine

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The free radical scavenger WR1065 (SH) is the active thiol form of the clinically approved cytoprotector amifostine. At doses of 40 μM and 4 mM it can activate the redox-sensitive nuclear transcription factor κB (NFκB) and elevate the expression of the antioxidant gene manganese superoxide dismutase (MnSOD) in human microvascular endothelial cells (HMEC). MnSOD contains binding motifs for a number of transcription factors other than NFκB and codes for a potent antioxidant enzyme localized in the mitochondria that is known to confer enhanced radiation resistance to cells. The purpose of this study was to determine the effect of WR1065 exposure on the various transcription factors known to affect MnSOD expression along with the subsequent kinetics of intracellular elevation of MnSOD protein levels and associated change in sensitivity to ionizing radiation in HMEC. Cells were grown to confluence and exposed to WR1065 for 30 min. Affects on the transcription factors AP1, AP2, CREB, NFκB, and Sp1 were monitored as a function of time ranging from 30 min to 4 h after drug exposure using a gel-shift assay. Only NFκB exhibited a marked activation and that occurred 30 min following the cessation of drug exposure. MnSOD protein levels, as determined by Western blot analysis, increased up to 16-fold over background control levels by 16 h following drug treatment, and remained at 10-fold or higher levels for an additional 32 h. MnSOD activity was evaluated using a gel-based assay and was found to be active throughout this time period. HMEC were irradiated with X-rays either in the presence of 40 μM or 4 mM WR1065 or 24 h after its removal when MnSOD levels were most elevated. No protection was observed for cells irradiated in the presence of 40 μM WR1065. In contrast, a 4 mM dose of WR1065 afforded an increase in cell survival by a factor of 2. A "delayed radioprotective" effect was, however, observed when cells were irradiated 24 h later, regardless of the concentration of WR1065 used. This effect is characterized as an increase in survival at the 2 Gy dose point, i.e., a 40% increase in survival, and an increase in the initial slope of the survival curve by a factor of 2. The anti-inflammatory sesquiterpene lactone, Helenalin, is an effective inhibitor of NFκB activation. HMEC were exposed to Helenalin for 2 h at a nontoxic concentration of 5 μM prior to exposure to WR1065. This treatment not only inhibited activation of NFκB by WR1065, but also inhibited the subsequent elevation of MnSOD and the delayed radioprotective effect. A persistent marked elevation of MnSOD in cells following their exposure to a thiol-containing reducing agent such as WR1065 can result in an elevated resistance to the cytotoxic effects of ionizing radiation and represents a novel radioprotection paradigm.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

Section: Irradiation Conditions and Survival Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

Murley

Kataoka

Weydert

et al. 2006

Free Radical Biology and Medicine

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Emerging Nanotechnology and Advanced Materials for Cancer Radiation Therapy

et al. 2017

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Radiation therapy (RT) including external beam radiotherapy (EBRT) and internal radioisotope therapy (RIT) has been widely used for clinical cancer treatment. However, owing to the low radiation absorption of tumors, high doses of ionizing radiations are often needed during RT, leading to severe damages to normal tissues adjacent to tumors. Meanwhile, the RT efficacies are limited by different mechanisms, among which the tumor hypoxia-associated radiation resistance is a well-known one, as there exists hypoxia inside most solid tumors while oxygen is essential to enhance radiation-induced DNA damages. With the development in nanotechnology, there have been great interests in using nanomedicine strategies to enhance radiation responses of tumors. Nanomaterials containing high-Z elements to absorb radiation rays (e.g. X-ray) can act as radio-sensitizers to deposit radiation energy within tumors and promote treatment efficacy. Nanoscale carriers are able to deliver therapeutic radioisotopes into tumors for internal RIT, or chemotherapeutic drugs for synergistically combined chemo-radiotherapy. As uncovered in recent studies, the tumor microenvironment could be modulated by various nanomedicine approaches to overcome hypoxia-associated radiation resistance. Herein, the authors will summarize the applications of nanomedicine for RT cancer treatment, and pay particular attention to the latest development of 'advanced materials' for enhanced cancer RT.

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Radioprotective gene therapy through retroviral expression of manganese superoxide dismutase

Southgate

Sheard

Milsom

et al. 2006

The Journal of Gene Medicine

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Mitochondrial Localization of Superoxide Dismutase is Required for Decreasing Radiation-Induced Cellular Damage

Cited by 133 publications

References 37 publications

Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

Emerging Nanotechnology and Advanced Materials for Cancer Radiation Therapy

Radioprotective gene therapy through retroviral expression of manganese superoxide dismutase

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