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: Hee Jung Yang, HyeSook Youn, Ki Moon Seong, Young Ju Yun, Wanyeon Kim, Young Ha Kim, Ji Young Lee, Cha Soon Kim, Young-Woo Jin, BuHyun Youn
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 82 Issue 5 Pg. 524-34 (Sep 01 2011) ISSN: 1873-2968 [Electronic] England
• PMID: 21669192 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• 5-Lipoxygenase-Activating Proteins
• ALOX5AP protein, human
• Benzofurans
• Coumarins
• Cyclooxygenase 2 Inhibitors
• Lipoxygenase Inhibitors
• NF-kappa B
• Radiation-Protective Agents
• Arachidonate 5-Lipoxygenase
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• psoralidin

Topics

• 5-Lipoxygenase-Activating Proteins (physiology)
• Animals
• Arachidonate 5-Lipoxygenase (physiology)
• Benzofurans (pharmacology)
• Cells, Cultured
• Coumarins (pharmacology)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Humans
• Lipoxygenase Inhibitors (pharmacology)
• Lung (radiation effects)
• Male
• Mice
• Mice, Inbred BALB C
• NF-kappa B (physiology)
• Phosphatidylinositol 3-Kinases (physiology)
• Pneumonia (etiology, prevention & control)
• Proto-Oncogene Proteins c-akt (physiology)
• Radiation-Protective Agents (pharmacology)