Amifostine protection against induced DNA damage in γ‐irradiated <i>Escherichia coli</i> cells depend on <i>recN</i> DNA repair gene product activity

Almeida, Eliseo; Fuentes, Jorge Luı́s; Cuétara, Elizabeth; Prieto, E.; Llagostera, Montserrat

doi:10.1002/tox.20483

Cited by 6 publications

(7 citation statements)

References 34 publications

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“…It has been known that amifostine/WR-1065 can directly support DNA repair (Figure 10) by donating hydrogen atoms and depleting oxygen to a singlet state. 53 Further, Almeida et al 20 revealed that the protection by amifostine against radiation-induced genotoxicity in Escherichia coli cells depends on the functional recN gene that is essential for the SOS response and repair of DSBs by homologous recombination. Dziegielewski et al 54 showed that WR-1065 prevents delayed genomic instability though, contrary to Almeida et al, 20 these authors suppose that WR-1065 disrupts homologous recombination and prevents its dangerous hyperstimulation by ionizing radiation.…”

Section: Resultsmentioning

confidence: 99%

“…Further, Almeida et al revealed that the protection by amifostine against radiation-induced genotoxicity in Escherichia coli cells depends on the functional recN gene that is essential for the SOS response and repair of DSBs by homologous recombination. Dziegielewski et al showed that WR-1065 prevents delayed genomic instability though, contrary to Almeida et al, these authors suppose that WR-1065 disrupts homologous recombination and prevents its dangerous hyperstimulation by ionizing radiation. In any case, direct interactions of the drug with p53, NFκB, ATM, and Tip60 (Xu et al), together with the modified expression of genes involved in DNA repair, cell cycle regulation, and apoptosis − confirm a more general influence of amifostine (and its metabolites) on DSB repair.…”

Section: Discussionmentioning

confidence: 99%

“…The most serious radiation-induced DNA damage is the double strand break (DSB) that causes a loss of the DNA molecule integrity. As DSB formation is also modulated by amifostine, , DSBs represent the most relevant type of DNA lesions in the context of amifostine-mediated cell radioprotection and radiosensitization. Molecular events following the ionizing radiation-induced DNA breakage include an immediate phosphorylation of histone H2AX (ser139), , which can be nowadays used to immunologically visualize the extent of DSB damage induction in intact cells as the so-called γH2AX foci within minutes after the DSB induction. − On the other hand, assessment of γH2AX foci disappearance during the postirradiation (PI) time allows monitoring of DSB repair.…”

Section: Introductionmentioning

confidence: 99%

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Two New Faces of Amifostine: Protector from DNA Damage in Normal Cells and Inhibitor of DNA Repair in Cancer Cells

et al. 2016

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Amifostine protects normal cells from DNA damage induction by ionizing radiation or chemotherapeutics, whereas cancer cells typically remain uninfluenced. While confirming this phenomenon, we have revealed by comet assay and currently the most sensitive method of DNA double strand break (DSB) quantification (based on γH2AX/53BP1 high-resolution immunofluorescence microscopy) that amifostine treatment supports DSB repair in γ-irradiated normal NHDF fibroblasts but alters it in MCF7 carcinoma cells. These effects follow from the significantly lower activity of alkaline phosphatase measured in MCF7 cells and their supernatants as compared with NHDF fibroblasts. Liquid chromatography-mass spectrometry confirmed that the amifostine conversion to WR-1065 was significantly more intensive in normal NHDF cells than in tumor MCF cells. In conclusion, due to common differences between normal and cancer cells in their abilities to convert amifostine to its active metabolite WR-1065, amifostine may not only protect in multiple ways normal cells from radiation-induced DNA damage but also make cancer cells suffer from DSB repair alteration.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Two New Faces of Amifostine: Protector from DNA Damage in Normal Cells and Inhibitor of DNA Repair in Cancer Cells

et al. 2016

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“…To date, amifostine has been applied for clinical protection against xerostomia during radiotherapy of head and neck cancer [103] . Interestingly, in addition to the radical scavenging, amifostine could also enhance DNA repair [104] and induce hypoxia [105] . Despite its approval and radioprotective effects (which are short term), amifostine is limited in use due its cumulative toxicity that is expressed as transient hypotension, nausea, vomit and allergic reactions.…”

Section: Ra Its Categoris and Mechanisms Of Functionmentioning

confidence: 99%

Research and Development of Radioprotective Agents: A Mini-Review

Saaya

Katsube

Xie

et al. 2017

International Journal of Radiology

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The research and development (R&D) of radioprotective agents (RAs) have been conducting since seven decades ago, and the safety and protection against undesirable effects of ionizing radiation (IR) has become an important issue especially for the benefit of patients receiving the radiotherapy, in addition to the applications in nuclear industry, military, outer space exploration and accidental exposures. Although the technology advancement makes the radiotherapy a promising better treatment by maximizing the effect of IR to the cancer cells, there are still needs for improvement in minimizing the toxicity to the normal cells. Aiming at providing the new researchers in the radiation protection field with an overall view for R&D of the RAs, this mini-review elucidates in brief a general understanding of the IR and its effects on the cell, the concepts of radiotherapy and therapeutic ratio, the categories of RAs and their mechanisms, and discusses on the strategies and challenge for R&D of the RAs.

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“…It was concluded that the radioprotective action of aminothiols may be mediated through a recombination-like mechanism, for which the diploid state and HR proficiency are required. A more recent study (42) demonstrated that the RecN gene product is required for amifostine-mediated DNA protection in E. coli cells. RecN protein is involved in homologous recombination, DSB repair (43), and structural maintenance of E. coli chromosome (44).…”

Section: Discussionmentioning

confidence: 99%

Amifostine Metabolite WR-1065 Disrupts Homologous Recombination in Mammalian Cells

et al. 2010

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Repair of DNA damage through homologous recombination (HR) pathways plays a crucial role in maintaining genome stability. However, overstimulation of HR pathways in response to genotoxic stress may abnormally elevate recombination frequencies, leading to increased mutation rates and delayed genomic instability. Radiation-induced genomic instability has been detected after exposure to both low- and high-linear energy transfer (LET) radiations, but the mechanisms responsible for initiating or propagating genomic instability are not known. We have demonstrated that WR-1065, the active metabolite of amifostine, protects against radiation-induced cell killing and delayed genomic instability. We hypothesize that hyperstimulation of HR pathways plays a mechanistic role in radiation-induced genomic instability and that, in part, WR-1065 exerts it radioprotective effect through suppression of the HR pathway. Results of this study demonstrate that WR-1065 treatment selectively protected against radiation-induced cell killing in HR-proficient cell lines compared to an HR-deficient cell line. Further, WR-1065 treatment decreases HR in response to DNA damage using two different mammalian cell systems. This suppression of hyper-recombination is a previously unrecognized mechanism by which WR-1065 effects radioprotection in mammalian cells.

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Amifostine protection against induced DNA damage in γ‐irradiated Escherichia coli cells depend on recN DNA repair gene product activity

Cited by 6 publications

References 34 publications

Two New Faces of Amifostine: Protector from DNA Damage in Normal Cells and Inhibitor of DNA Repair in Cancer Cells

Two New Faces of Amifostine: Protector from DNA Damage in Normal Cells and Inhibitor of DNA Repair in Cancer Cells

Research and Development of Radioprotective Agents: A Mini-Review

Amifostine Metabolite WR-1065 Disrupts Homologous Recombination in Mammalian Cells

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