PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2.
Radiation-induced gastrointestinal (GI) toxicity can be a major source of morbidity and mortality after radiation exposure. There is an unmet need for effective preventative or mitigative treatments against the potentially fatal diarrhea and water loss induced by radiation damage to the GI tract. We report that prolyl hydroxylase inhibition by genetic knockout or pharmacologic inhibition of all PHD (prolyl hydroxylase domain) isoforms by the small-molecule dimethyloxallyl glycine (DMOG) increases hypoxia-inducible factor (HIF) expression, improves epithelial integrity, reduces apoptosis, and increases intestinal angiogenesis, all of which are essential for radioprotection. HIF2, but not HIF1, is both necessary and sufficient to prevent radiation-induced GI toxicity and death. Increased vascular endothelial growth factor (VEGF) expression contributes to the protective effects of HIF2, because inhibition of VEGF function reversed the radioprotection and radiomitigation afforded by DMOG. Additionally, mortality from abdominal or total body irradiation was reduced even when DMOG was given 24 hours after exposure. Thus, prolyl hydroxylase inhibition represents a treatment strategy to protect against and mitigate GI toxicity from both therapeutic radiation and potentially lethal radiation exposures.
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
Cullen M
CM
Taniguchi
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
Yu Rebecca
YR
Miao
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
Anh N
AN
Diep
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
Colleen
C
Wu
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
Erinn B
EB
Rankin
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
Todd F
TF
Atwood
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
Lei
L
Xing
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA. giaccia@stanford.edu.
Amato J
AJ
Giaccia
D000600:Amino Acids, Dicarboxylic / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry* / Q000235:genetics*; D001835:Body Weight; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000528:radiation effects; D005786:Gene Expression Regulation; D006400:Hematocrit; D006579:Heterozygote; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D064800:Prolyl-Hydroxylase Inhibitors / Q000737:chemistry; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D017434:Protein Structure, Tertiary; D011832:Radiation Injuries / Q000188:drug therapy* / Q000517:prevention & control; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry; D000099162:Endothelial PAS Domain-Containing Protein 1
D000600:Amino Acids, Dicarboxylic; D051792:Basic Helix-Loop-Helix Proteins; D002614:Chelating Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064800:Prolyl-Hydroxylase Inhibitors; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C040947:oxalylglycine