Dehydrocostuslactone, a medicinal plant-derived sesquiterpene lactone, induces apoptosis coupled to endoplasmic reticulum stress in liver cancer cells.

Abstract

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.

• Authors: Ya-Ling Hsu, Ling-Yu Wu, Po-Lin Kuo
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 329 Issue 2 Pg. 808-19 (May 2009) ISSN: 1521-0103 [Electronic] United States
• PMID: 19188481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Lactones
• Sesquiterpenes
• dehydrocostus lactone
• Caspases
• Calcium

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Calcium (metabolism)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Endoplasmic Reticulum (drug effects, metabolism)
• Humans
• Immunoblotting
• Lactones (pharmacology, therapeutic use)
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• Oxidative Stress (drug effects)
• Reverse Transcriptase Polymerase Chain Reaction
• Saussurea (chemistry)
• Sesquiterpenes (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays