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 NH2-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.
Footnotes
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This work was supported by the National Science Council of Taiwan [Research Grant NSC 96-2628-B-041-001-MY3].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.148395.
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ABBREVIATIONS: HCC, hepatocellular carcinoma; ER, endoplasmic reticulum; UPR, unfolded protein response; IRE1, inositol-requiring protein 1; PERK, double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase; ATF6, activating transcription factor 6; eIF-2α, eukaryotic translation initiation factor-2α; XBP-1, X-box transcription factor-1; DHE, dehydrocostuslactone, (3aS,6aR,9aR,9bS)-decahydro-3,6,9-tris(methylene) azuleno[4,5-b]furan-2(3H)-one); MAPK, mitogen-activated protein kinase; DMSO, dimethyl sulfoxide; XTT, sodium 3′-[1-(phenylamino-carbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene-sulfonic acid hydrate; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; AIF, apoptosis-inducing factor; RT, reverse transcriptase; PCR, polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; AM, acetoxymethyl ester; PBS, phosphate-buffered saline; siRNA, small interfering RNA; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; Endo G, endonuclease G; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imadazole; PD98059, 2′-amino-3′-methoxyflavone; SP600125, 1,9-pyrazoloanthrone; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; CHO, Chinese hamster ovary.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received November 6, 2008.
- Accepted January 30, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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