Department of Biological Sciences, College of Natural Sciences, Pusan National University, 30 Jangjeon-dong, Geumjeong-gu, Busan, Republic of Korea.
Biochem Pharmacol. 2011 Sep 1;82(5):524-34. doi: 10.1016/j.bcp.2011.05.027. Epub 2011 Jun 2.
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.
放射疗法是消除肿瘤的最主要非手术治疗方法，然而它受到两个主要问题的限制：放射抗性和正常组织损伤。需要提高放射疗法的效率，以实现癌症治疗。我们专注于放射诱导的正常细胞损伤，并关注炎症，据报道炎症是放射疗法的主要限制因素之一。补骨脂素是从补骨脂种子中分离出来的香豆素衍生物，已被研究用于抗癌和抗菌特性。然而，关于其对 IR 诱导的肺部炎症的影响知之甚少。本研究旨在探讨 IR 诱导炎症的机制，并研究补骨脂素在人正常肺成纤维细胞和小鼠中的治疗机制。在这里，我们证明了 IR 诱导的 ROS 激活了 HFL-1 和 MRC-5 细胞中的环氧化酶-2（COX-2）和 5-脂氧合酶（5-LOX）途径。补骨脂素通过调节 PI3K/Akt 和 NF-κB 途径抑制 IR 诱导的 COX-2 表达和 PGE（2）产生。此外，补骨脂素阻断了 IR 诱导的 LTB（4）产生，这是由于补骨脂素与 5-LOX 途径中的 5-脂氧合酶激活蛋白（FLAP）的直接相互作用。IR 诱导的成纤维细胞迁移在补骨脂素存在下明显减弱。此外，来自小鼠肺的体内结果表明，补骨脂素抑制了 IR 诱导的促炎细胞因子（TNF-α、TGF-β、IL-6 和 IL-1α/β）和 ICAM-1 的表达。总之，我们的研究结果揭示了人正常肺成纤维细胞和小鼠中 IR 诱导的肺部炎症的调节机制，并表明补骨脂素可能作为一种有前途的先导化合物，用于开发更好的放射预防剂，以防止辐射引起的正常组织损伤。
