Open AccessRadiation mitigation of the intestinal acute radiation injury in mice by 1‐[(4‐nitrophenyl)sulfonyl]‐4‐phenylpiperazine
Author(s) -
DuhachekMuggy Sara,
Bhat Kruttika,
Medina Paul,
Cheng Fei,
He Ling,
Alli Claudia,
Saki Mohammad,
Muthukrishnan Sree Deepthi,
Ruffenach Gregoire,
Eghbali Mansoureh,
Vlashi Erina,
Pajonk Frank
Publication year - 2020
Publication title -
stem cells translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.781
H-Index - 71
eISSN - 2157-6580
pISSN - 2157-6564
DOI - 10.1002/sctm.19-0136
Subject(s) - acute radiation syndrome , ionizing radiation , medicine , radiation therapy , cancer research , pharmacology , stem cell , haematopoiesis , biology , irradiation , microbiology and biotechnology , physics , nuclear physics
The objective of the study was to identify the mechanism of action for a radiation mitigator of the gastrointestinal (GI) acute radiation syndrome (ARS), identified in an unbiased high‐throughput screen. We used mice irradiated with a lethal dose of radiation and treated with daily injections of the radiation mitigator 1‐[(4‐nitrophenyl)sulfonyl]‐4‐phenylpiperazine to study its effects on key pathways involved in intestinal stem cell (ISC) maintenance. RNASeq, quantitative reverse transcriptase‐polymerase chain reaction, and immunohistochemistry were performed to identify pathways engaged after drug treatment. Target validation was performed with competition assays, reporter cells, and in silico docking. 1‐[(4‐Nitrophenyl)sulfonyl]‐4‐phenylpiperazine activates Hedgehog signaling by binding to the transmembrane domain of Smoothened, thereby expanding the ISC pool, increasing the number of regenerating crypts and preventing the GI‐ARS. We conclude that Smoothened is a target for radiation mitigation in the small intestine that could be explored for use in radiation accidents as well as to mitigate normal tissue toxicity during and after radiotherapy of the abdomen.