Hsu Ya-Ling, Wu Ling-Yu, Kuo Po-Lin
Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
J Pharmacol Exp Ther. 2009 May;329(2):808-19. doi: 10.1124/jpet.108.148395. Epub 2009 Feb 2.
This study is the first to investigate the anticancer effect of dehydrocostuslactone [DHE (3aS,6aR,9aR,9bS)-decahydro-3,6,9-tris(methylene) azuleno[4,5-b]furan-2(3H)-one)], a medicinal plant-derived sesquiterpene lactone, on hepatocellular carcinoma. Our results showed that DHE inhibits the proliferation of HepG2 and PLC/PRF/5 cells by inducing apoptosis. DHE induces up-regulation of Bax and Bak, down-regulation of Bcl-2 and Bcl-XL, and nuclear relocation of the mitochondrial factors apoptosis-inducing factor (AIF) and endonuclease G (Endo G). DHE triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol-calcium levels, double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase phosphorylation, inositol-requiring protein 1 (IRE1) and CHOP/GADD153 up-regulation, X-box transcription factor-1 mRNA splicing, and caspase-4 activation. Enhancement of ER stress by DHE is through p38 and extracellular signal-regulated kinase 1/2-dependent manners and subsequently causes c-Jun NH(2)-terminal kinase activation, resulting in AIF and Endo G nuclear relocation. Both of IRE1 small interfering RNA transfection and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester pretreatment inhibit DHE-mediated apoptosis, supporting the hypothesis that DHE induces cell death through ER stress. It is noteworthy that animal studies have revealed a dramatic 50% reduction in tumor volume after 45 days of treatment. This study demonstrates that DHE may be a novel anticancer agent for the treatment of liver cancer.
本研究首次调查了去氢木香内酯[DHE（3aS，6aR，9aR，9bS）-十氢-3,6,9-三（亚甲基）薁并[4,5-b]呋喃-2（3H）-酮]，一种源自药用植物的倍半萜内酯，对肝细胞癌的抗癌作用。我们的结果表明，DHE通过诱导凋亡来抑制HepG2和PLC/PRF/5细胞的增殖。DHE诱导Bax和Bak上调，Bcl-2和Bcl-XL下调，以及线粒体因子凋亡诱导因子（AIF）和核酸内切酶G（Endo G）的核转位。DHE引发内质网（ER）应激，表现为胞质钙水平变化、双链RNA激活的蛋白激酶样内质网激酶磷酸化、肌醇需求蛋白1（IRE1）和CHOP/GADD153上调、X盒转录因子-1 mRNA剪接以及半胱天冬酶-4激活。DHE增强ER应激是通过p38和细胞外信号调节激酶1/2依赖性方式，随后导致c-Jun NH（2）-末端激酶激活，从而导致AIF和Endo G核转位。IRE1小干扰RNA转染和1,2-双（2-氨基苯氧基）乙烷-N，N，N'，N'-四乙酸-乙酰氧甲酯预处理均抑制DHE介导的凋亡，支持DHE通过ER应激诱导细胞死亡的假说。值得注意的是，动物研究显示治疗45天后肿瘤体积显著减少了50%。本研究表明，DHE可能是一种治疗肝癌的新型抗癌药物。
