4-(Nitrophenylsulfonyl)piperazines mitigate radiation damage to multiple tissues

• Published in: PloS one Vol. 12; no. 7; p. e0181577
• Main Authors: Micewicz, Ewa D, Kim, Kwanghee, Iwamoto, Keisuke S, Ratikan, Josephine A, Cheng, Genhong, Boxx, Gayle M, Damoiseaux, Robert D, Whitelegge, Julian P, Ruchala, Piotr, Nguyen, Christine, Purbey, Prabhat, Loo, Joseph, Deng, Gang, Jung, Michael E, Sayre, James W, Norris, Andrew J, Schaue, Dörthe, McBride, William H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.07.2017; Public Library of Science (PLoS)
• Subjects: Acute Radiation Syndrome - drug therapy; Animal models; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - radiation effects; Biochemistry; Biology and Life Sciences; Bone marrow; Cancer; Cancer therapies; CD11b antigen; Cells, Cultured; Chemical compounds; Chemistry; Death; DNA damage; Energy consumption; Euthanasia; Female; Fibrosis; Health aspects; Hemopoiesis; Immunology; In vitro methods and tests; Inhibitors; Ionizing radiation; Irradiation; Laboratories; Lead; Lethality; Lung cancer; Male; Mass spectrometry; Medicine and Health Sciences; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mitigation; Myeloid cells; Myeloid Cells - drug effects; Myeloid Cells - radiation effects; Oncology; Pharmacology; Physical Sciences; Piperazines - pharmacology; Pneumonitis; Radiation; Radiation damage; Radiation effects; Radiation injuries; Radiation therapy; Radiotherapy; Risk factors; Rodents; Scientific imaging; Stem cells; Thorax; Tissues; Los Angeles California; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0181577

Our ability to use ionizing radiation as an energy source, as a therapeutic agent, and, unfortunately, as a weapon, has evolved tremendously over the past 120 years, yet our tool box to handle the consequences of accidental and unwanted radiation exposure remains very limited. We have identified a novel group of small molecule compounds with a 4-nitrophenylsulfonamide (NPS) backbone in common that dramatically decrease mortality from the hematopoietic acute radiation syndrome (hARS). The group emerged from an in vitro high throughput screen (HTS) for inhibitors of radiation-induced apoptosis. The lead compound also mitigates against death after local abdominal irradiation and after local thoracic irradiation (LTI) in models of subacute radiation pneumonitis and late radiation fibrosis. Mitigation of hARS is through activation of radiation-induced CD11b+Ly6G+Ly6C+ immature myeloid cells. This is consistent with the notion that myeloerythroid-restricted progenitors protect against WBI-induced lethality and extends the possible involvement of the myeloid lineage in radiation effects. The lead compound was active if given to mice before or after WBI and had some anti-tumor action, suggesting that these compounds may find broader applications to cancer radiation therapy.