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

Abstract

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.

Radiation mitigation of the intestinal acute radiation injury in mice by 1-[(4-nitrophenyl)sulfonyl]-4-phenylpiperazine

“…35 In mouse models of inflammatory bowel disease Hedgehog signaling in stromal cells at the base of the crypt leads to increased IL-10 production as a major anti-inflammatory mechanism. 33 This is in agreement with our observation that compound #5 not only mitigated the GI-ARS but also led to increased cellularity in the germinal centers of Peyer's patches, 21 prevented hematopoietic ARS, 12 increased the number of peripheral CD11b + Ly6C + Ly6G + myeloid cells and stimulated IL-10 production. 12…”

“…33 This is in agreement with our observation that compound #5 not only mitigated the GI-ARS but also led to increased cellularity in the germinal centers of Peyer's patches, 21 prevented hematopoietic ARS, 12 increased the number of peripheral CD11b + Ly6C + Ly6G + myeloid cells and stimulated IL-10 production. 12…”

“…Countermeasures against Radiation identified compounds with radiation mitigator properties to the hematopoietic system and the gut. 11,12 Among these compounds, 1-[(4-nitrophenyl)sulfonyl]-4-phenylpiperazine (compound #5; Figure 1A) most efficiently mitigated hematopoietic and GI-ARS. However, the underlying mechanisms of action were not investigated 12 and are addressed in our present study.…”

A Preview of Selected Articles

“…The rapid loss of the integrity of the epithelial layer lining the intestines represents a characteristic gastrointestinal feature of ARS, a lethal condition associated with the exposure to even moderate doses of radiation. However, a previous unbiased high-throughput screening study identified a piperazine compound (1-[(4-nitrophenyl)sulfonyl]-4-phenylpiperazine) as a potential mitigator of ARS in the gastrointestinal system, 16 while also identifying a compound that protected the hematopoietic system. 17 Researchers from the laboratory of Frank Pajonk (University of California, Los Angeles, USA) sought to follow up these encouraging findings by exploring the mechanism of action of this piperazine radiation mitigating compound.…”

A Preview of Selected Articles

“…The rapid loss of the integrity of the epithelial layer lining the intestines represents a characteristic gastrointestinal feature of ARS, a lethal condition associated with the exposure to even moderate doses of radiation. However, a previous unbiased high‐throughput screening study identified a piperazine compound (1‐[(4‐nitrophenyl)sulfonyl]‐4‐phenylpiperazine) as a potential mitigator of ARS in the gastrointestinal system, while also identifying a compound that protected the hematopoietic system . Researchers from the laboratory of Frank Pajonk (University of California, Los Angeles, USA) sought to follow up these encouraging findings by exploring the mechanism of action of this piperazine radiation mitigating compound .…”