IKKβ Inhibitor IMD-0354 Attenuates Radiation Damage in Whole-body X-Irradiated Mice.

Kengo Waga,Masaru Yamaguchi,Shuta Miura,Ikuo Kashiwakura,Reiko Nakanishi,Teruki Nishida,Akiko Itai

doi:10.1155/2019/5340290

Abstract

Nuclear factor-kappa B (NF-κB) transcription factor plays a critical role in regulating radiation-induced inflammatory and immune responses. Intracellular reactive oxygen species generation induces the activation of NF-κB via the inhibitor of κB (IκB) kinase (IKK) complex signaling. Previous studies have reported that the inhibition of IKK-driven NF-κB activation offers a therapeutic strategy for managing inflammatory disorders and various cancers, but it has additionally been reported that treatment targeting NF-κB also shows a radioprotective effect. IMD-0354 is an IKKβ inhibitor that blocks IκBα phosphorylation in the NF-κB pathway. This compound is known to exert anti-inflammatory and antitumor effects, but its radioprotective effects are unclear. Therefore, in the present study, we examined whether or not IMD-0354 has a mitigative effect on radiation-induced damages in mice. IMD-0354 was dissolved in soybean oil and subcutaneously administered to C57BL/6J Jcl mice for 3 consecutive days after 7 Gy of whole-body X-irradiation. The survival rate on day 30 and the NF-κB p65 and IκBα in bone marrow and spleen cells based on flow cytometry were assessed. IMD-0354 administration significantly suppressed the lethality induced by whole-body X-irradiation, and the survival rate increased by 83%. The NF-κB p65 and IκBα in bone marrow and spleen cells were significantly lower in IMD-0354-treated mice than in irradiated mice, suggesting that the IKKβ inhibitor IMD-0354 exerts a radiomitigative effect by suppressing the NF-κB.

Highlights

Nuclear factor-kappa B (NF-κB) is involved in many physiological phenomena such as immune reaction and cell death, as well as in the regulation of cell proliferation and apoptosis [1]
IMD-0354 was subcutaneously administered to wholebody X-irradiated mice for 3 days, and the survival rate was evaluated over 30 days (Figure 1)
In the irradiated mice without IMD-0354 administration, individual death was observed from day 12 after irradiation and the survival rate on day 30 was 40%

Summary

Introduction

Nuclear factor-kappa B (NF-κB) is involved in many physiological phenomena such as immune reaction and cell death, as well as in the regulation of cell proliferation and apoptosis [1]. Activation of the inhibitor of κB (IκB) kinase (IKK) complex signaling occurs in response to extracellular stresses such as radiation, inflammation, and reactive oxygen species [2]. Activation of IKKβ which is a part of the IKK complex mainly occurs in the canonical NF-κB pathway [3]. NF-κB is usually present in the cytoplasm in association with IκBα that suppresses the nuclear translocation of NF-κB, but activation of IKKβ causes phosphorylation of IκBα by serine residues [4, 5]. Phosphorylated IκBα is ubiquitinated and becomes the target of degradation by the 26S proteasome, and NF-κB detached from IκBα migrates into the nucleus and binds to DNA, resulting in the gene expression of inflammatory proteins, antiapoptotic proteins, or cell-adhesion molecules [5,6,7,8]. Since NF-κB is constitutively activated in many cancer cells, several studies have evaluated substances targeting NF-κB as anticancer agents [9, 10]

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Results

Conclusion