Amelioration of Radiation-Induced Pulmonary Fibrosis by a Water-Soluble Bifunctional Sulfoxide Radiation Mitigator (MMS350)

Abstract

A water-soluble ionizing radiation mitigator would have considerable advantages for the management of acute and chronic effects of ionizing radiation. We report that a novel oxetanyl sulfoxide (MMS350) is effective both as a protector and a mitigator of clonal mouse bone marrow stromal cell lines in vitro, and is an effective in vivo mitigator when administered 24 h after 9.5 Gy (LD100/30) total-body irradiation of C57BL/6NHsd mice, significantly improving survival (P =0.0097). Furthermore, MMS350 (400 μM) added weekly to drinking water after 20 Gy thoracic irradiation significantly decreased: expression of pulmonary inflammatory and profibrotic gene transcripts and proteins; migration into the lungs of bone marrow origin luciferase+/GFP+ (luc+/GFP+) fibroblast progenitors (in both luc+ marrow chimeric and luc+ stromal cell line injected mouse models) and decreased radiation-induced pulmonary fibrosis (P < 0.0001). This nontoxic and orally administered small molecule may be an effective therapeutic in clinical radiotherapy and as a counter measure against the acute and chronic effects of ionizing radiation.

Induction of TGF-β by Irradiation or Chemotherapy in Fanconi Anemia (FA) Mouse Bone Marrow Ιs Modulated by Small Molecule Radiation Mitigators JP4-039 and MMS350

“…The present data establish that the radiation mitigator drugs, JP4-039 (27-31) and MMS350 (32)(33), each modulate the induction of TGF-β by cytotoxic agents in cell lines in vitro. The TGF-β inhibitor, LY364947 also modulated irradiation or drug induced TGF-β in vitro with fresh marrow hematopoietic colony forming cells.…”

“…The radiation mitigator drugs JP4-039 (30) and MMS350 (32) were each tested for mechanism of action in vitro, specifically for effects of 5-Gy irradiation on autophagy compared to apoptosis in vitro using 32D cl 3 cells (36). In vitro JP4-039 was dissolved in DMSO (26), and MMS350 (32) dissolved in water.…”

“…Inflammatory cytokines including: TNF-α, and IL-1 are induced by irradiation of the oral cavity/oropharyngeal tissue and the irradiated lung (32,(38)(39). Other categories of biomarkers that are induced by irradiation include genes for proteins that bind to DNA and act as gene transcription promoters, such as NFkβ, Nrf1, AP-1, and SP-1 (32).…”

“…Inflammatory cytokines including: TNF-α, and IL-1 are induced by irradiation of the oral cavity/oropharyngeal tissue and the irradiated lung (32,(38)(39). Other categories of biomarkers that are induced by irradiation include genes for proteins that bind to DNA and act as gene transcription promoters, such as NFkβ, Nrf1, AP-1, and SP-1 (32). Whether some of these other induced gene products neutralize, counteract, or synergize with elevated TGF-β in FA patients to either suppress or exacerbate the hyperactive TGF-β responses and how these other gene products relate to the specific categories of toxicity in bone marrow transplant recipients is unknown.…”

“…We evaluated the effect of radiation mitigator drugs JP4-039 (29) and MMS350 (32) as well as of the chemotherapeutic agents, L-phenylalanine mustard (L-PAM), busulfan and Fludarabine, on TGF-β induction. The results demonstrated that TGF-β expression was inducible by irradiation and by either of the three chemotherapeutic drugs in vitro and in vivo.…”