Reducing radiation-induced gastrointestinal toxicity — the role of the PHD/HIF axis

Olcina, Monica M.; Giaccia, Amato J.

doi:10.1172/jci84432

Cited by 56 publications

(55 citation statements)

References 96 publications

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“…Unfortunately, few safe and effective drugs exist for the treatment of radiation‐induced injury. Recently, it was reported that PHD inhibition mitigated and protected against radiation‐induced gastrointestinal toxicity . It was demonstrated that PHD inhibitor (DMOG) could protect against supralethal doses of ionizing radiation to the abdomen or whole body through up‐regulating hypoxia‐inducible factor‐2 (HIF‐2) .…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that roxadustat, also known as FG‐4592, is a first‐in‐class small molecule oral PHD inhibitor, which is currently used for the treatment of anaemia in patients with chronic kidney disease(CKD) in phase III clinical trials . So we evaluated the effects of FG‐4592 in radioprotection, which may facilitate its use as a protector after large‐scale accidental radiation incidents or as part of radiotherapy treatment in the future …”

Section: Discussionmentioning

confidence: 99%

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Radioprotective effects of roxadustat (FG‐4592) in haematopoietic system

Zhang

Zhao

et al. 2018

J Cellular Molecular Medi

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BackgroundIonizing radiation often causes severe injuries to radiosensitive tissues, especially haematopoietic system. Novel radioprotective drugs with low toxicity and high effectiveness are required. Prolyl hydroxylases domain (PHD) inhibitors have been reported to protect against radiation‐induced gastrointestinal toxicity. In this study, we demonstrated the protective effects of a PHD inhibitor, roxadustat (FG‐4592), against radiation‐induced haematopoietic injuries in vitro and in vivo.MethodsTissue injuries were evaluated by Haematoxilin‐Eosin (HE) staining assay. HSCs were determined by flow cytometry with the Lin−Sca‐1+c‐Kit+ (LSK) phenotype. Cell apoptosis was determined by Annexin V/PI staining assay. Immunofluorescence was performed to measure radiation‐induced DNA damage. A western blot assay was used to detect the changes of proteins related to apoptosis.ResultsWe found that FG‐4592 pretreatment increased survival rate of irradiated mice and protected bone marrow and spleen from damages. Number of bone marrow cells (BMCs) and LSK cells were also increased both in irradiated mice and recipients after bone marrow transplantation (BMT). FG‐4592 also protected cells against radiation‐induced apoptosis and double strand break of DNA.ConclusionsOur data showed that FG‐4592 exhibited radioprotective properties in haematopoietic system both in vivo and in vitro through up‐regulating HIF‐1α, indicating a potential role of FG‐4592 as a novel radioprotector.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Radioprotective effects of roxadustat (FG‐4592) in haematopoietic system

Zhang

Zhao

et al. 2018

J Cellular Molecular Medi

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“…TBI causes many side-effects, including nausea, diarrhoea, sensitive skin and hair loss, that are temporary. However, TBI can also cause severe long-term damage to several organs, such as the lung, trachea and mouth (radiation-induced pneumonitis, fibrosis, oral mucositis) (Marks et al, 2003;Mehta, 2005), reproductive system (radiation-induced infertility) (Ogilvy-Stuart and Shalet, 1993), liver (radiation-induced liver disease) (Kim and Jung, 2017), gastro-intestinal tract (radiation-induced gastric mucositis, radiation-induced gastro intestinal syndrome) (Francois et al, 2013;Olcina and Giaccia, 2016) or kidney (radiation-induced nephropathy) (Cohen, 2000;Cohen and Robbins, 2003). Furthermore, TBI can also initiate secondary malignancies (Dracham et al, 2018).…”

Section: Impact Of Induced Deletion Of Bcl-xl In Adult Micementioning

confidence: 99%

“…Moreover, a robust inflammatory response is observed upon radiation-induced damage to the gastro-intestinal tract (Olcina and Giaccia, 2016). Pro-inflammatory cytokines (e.g.…”

Section: Impact Of Induced Deletion Of Bcl-xl In Adult Micementioning

confidence: 99%

BCL-XL is essential for the protection from secondary anemia caused by radiation-induced fatal kidney damage

Brinkmann

Waring

Glaser

et al. 2020

Preprint

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The inducible loss of BCL-XL in all cells of adult mice causes primary anemia due to apoptosis of erythroid and megakaryocytic cell populations. In contrast g-radiation plus loss of BCL-XL in all cells except hematopoietic cells causes secondary anemia resulting from kidney damage. AbstractStudies of gene-targeted mice identified the roles of the different pro-survival BCL-2 proteins during embryogenesis, but less is known about the roles of these proteins in adults, including in the response to cytotoxic stresses, such as treatment with anti-cancer agents. We investigated the role of BCL-XL in adult mice using a strategy where prior bone marrow transplantation allowed for loss of BCL-XL exclusively in non-hematopoietic tissues to prevent anemia caused by BCL-XL-deficiency in erythroid cells. Unexpectedly, the combination of total-body g-irradiation (TBI) and genetic loss of Bcl-x caused secondary anemia resulting from chronic renal failure due to apoptosis of renal tubular epithelium with secondary obstructive nephropathy. These findings identify a critical protective role of BCL-XL in the adult kidney and inform on the use of BCL-XL inhibitors in combinations with DNA damage-inducing drugs for cancer therapy.

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“…expressivos. O uso de inibidores químicos têm resultados estabilizadores dos fatores que levam a hipóxia celular, estabelecendo uma nova modalidade de radioprotetores[9]. efeitos a longo prazo não são prejudiciais a hematopoiese segundo estudo americano de 2018[13].Análises matemáticas são atualmente utilizados para scores clinicos frente a exposição de altas doses, oferecendo dinâmica em varias diretrizes de diagnósticos, inclusive das células sanguineas.…”

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