PHD Inhibition Mitigates and Protects Against Radiation-Induced Gastrointestinal Toxicity via HIF2

Abstract

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 isoforms by the small molecule dimethyloxyallylglycine (DMOG) increases 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 VEGF expression contributes to the protective effects of HIF2, since inhibition of VEGF function reversed the radioprotection and radiomitigation afforded by DMOG. Additionally, mortality is reduced from abdominal or total body irradiation even when DMOG is given 24 hours after exposure. Thus, prolyl hydroxylase inhibition represents a new treatment strategy to protect against and mitigate GI toxicity from both therapeutic radiation and potentially lethal radiation exposures.

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

“…When the small molecule DMOG was used in combination with irradiation, HIF-1α and HIF-2α stabilization in the GI tract was significantly increased following DMOG and irradiation compared to irradiation alone (27). Interestingly, GI tract-specific genetic knockdown of all three PHDs was necessary for abundant HIF expression, while knockdown of individual PHDs had minimal effects.…”

“…The effects of irradiation alone on HIF stabilization in normal tissues appear complex, with HIF-1α and HIF-2α being detected in the colon, liver, and kidneys, but not in other organs such as the lung following irradiation (27). When the small molecule DMOG was used in combination with irradiation, HIF-1α and HIF-2α stabilization in the GI tract was significantly increased following DMOG and irradiation compared to irradiation alone (27).…”

“…mucosal protection in murine models of GI damage (26,27). FG-4497 was shown to protect the intestinal mucosa in models of chemical-induced colitis, while DMOG protects against radiation-induced toxicity (26,27). Both of these PHD inhibitors were shown to stabilize HIFs, resulting in the activation of downstream HIF target genes (26,27).…”

“…This complexity is reflected by a lack of arrows between events. mucosal protection in murine models of GI damage (26,27). FG-4497 was shown to protect the intestinal mucosa in models of chemical-induced colitis, while DMOG protects against radiation-induced toxicity (26,27).…”

“…Indeed, prolyl hydroxylase domain-containing enzyme (PHD) inhibitors, which stabilize HIF, have been recently described as a new class of agents that could reduce radiation-induced toxicity when given both before and up to 24 hours after irradiation in mice (27).…”