title: Psoralidin, a dual inhibitor of COX-2 and 5-LOX, regulates ionizing radiation (IR)-induced pulmonary inflammation.
abstract: Radiotherapy is the most significant non-surgical cure for the elimination of tumor, however it is restricted by two major problems: radioresistance and normal tissue damage. Efficiency improvement on radiotherapy is demanded to achieve cancer treatment. We focused on radiation-induced normal cell damage, and are concerned about inflammation reported to act as a main limiting factor in the radiotherapy. Psoralidin, a coumestan derivative isolated from the seed of Psoralea corylifolia, has been studied for anti-cancer and anti-bacterial properties. However, little is known regarding its effects on IR-induced pulmonary inflammation. The aim of this study is to investigate mechanisms of IR-induced inflammation and to examine therapeutic mechanisms of psoralidin in human normal lung fibroblasts and mice. Here, we demonstrated that IR-induced ROS activated cyclooxygenases-2 (COX-2) and 5-lipoxygenase (5-LOX) pathway in HFL-1 and MRC-5 cells. Psoralidin inhibited the IR-induced COX-2 expression and PGE(2) production through regulation of PI3K/Akt and NF-κB pathway. Also, psoralidin blocked IR-induced LTB(4) production, and it was due to direct interaction of psoralidin and 5-lipoxygenase activating protein (FLAP) in 5-LOX pathway. IR-induced fibroblast migration was notably attenuated in the presence of psoralidin. Moreover, in vivo results from mouse lung indicate that psoralidin suppresses IR-induced expression of pro-inflammatory cytokines (TNF-α, TGF-β, IL-6 and IL-1 α/β) and ICAM-1. Taken together, our findings reveal a regulatory mechanism of IR-induced pulmonary inflammation in human normal lung fibroblast and mice, and suggest that psoralidin may be useful as a potential lead compound for development of a better radiopreventive agent against radiation-induced normal tissue injury.
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Pusan National University, 30 Jangjeon-dong, Geumjeong-gu, Busan, Republic of Korea.
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Yang
authors.forename: HyeSook
authors.initials: H
authors.lastname: Youn
authors.forename: Ki Moon
authors.initials: KM
authors.lastname: Seong
authors.forename: Young Ju
authors.initials: YJ
authors.lastname: Yun
authors.forename: Wanyeon
authors.initials: W
authors.lastname: Kim
authors.forename: Young Ha
authors.initials: YH
authors.lastname: Kim
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Cha Soon
authors.initials: CS
authors.lastname: Kim
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Jin
authors.forename: BuHyun
authors.initials: B
authors.lastname: Youn
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins / Q000502:physiology; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology*; D001572:Benzofurans / Q000494:pharmacology*; D002478:Cells, Cultured; D003374:Coumarins / Q000494:pharmacology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011014:Pneumonia / Q000209:etiology / Q000517:prevention & control*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011837:Radiation-Protective Agents / Q000494:pharmacology*
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D001572:Benzofurans; D003374:Coumarins; D052246:Cyclooxygenase 2 Inhibitors; D016859:Lipoxygenase Inhibitors; D016328:NF-kappa B; D011837:Radiation-Protective Agents; D001094:Arachidonate 5-Lipoxygenase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C102768:psoralidin