Supercritical carbon dioxide extraction of aromatic turmerone from Curcuma longa Linn. Induces apoptosis through reactive oxygen species-triggered intrinsic and extrinsic pathways in human hepatocellular carcinoma HepG2 cells

Shao Bin Cheng, Li Chen Wu, Yun Chih Hsieh, Chi Hao Wu, Yu Ju Chan, Li Hsun Chang, Chieh Ming J Chang, Shih Lan Hsu, Chieh Lin Teng, Chun Chi Wu

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Abstract

The mechanisms underlying the antiproliferative and antitumor activities of aromatic turmerone (ar-turmerone), a volatile turmeric oil isolated from Curcuma longa Linn., have been largely unknown. In this study, 86% pure ar-turmerone was extracted by supercritical carbon dioxide and liquid-solid chromatography and its potential effects and molecular mechanisms on cell proliferation studied in human hepatocellular carcinoma cell lines. Ar-turmerone exhibited significant antiproliferative activity, with 50% inhibitory concentrations of 64.8 ± 7.1, 102.5 ± 11.5, and 122.2 ± 7.6 μg/mL against HepG2, Huh-7, and Hep3B cells, respectively. Ar-turmerone-induced apoptosis, confirmed by increased annexin V binding and DNA fragmentation, was accompanied by reactive oxygen species (ROS) production, mitochondrial membrane potential dissipation, increased Bax and p53 up-regulated modulator of apoptosis (PUMA) levels, Bax mitochondrial translocation, cytochrome c release, Fas and death receptor 4 (DR4) augmentation, and caspase-3, -8, and -9 activation. Exposure to caspase inhibitors, Fas-antagonistic antibody, DR4 antagonist, and furosemide (a blocker of Bax translocation) effectively abolished ar-turmerone-triggered apoptosis. Moreover, ar-turmerone stimulated c-Jun N-terminal kinase (JNK) and extracellular signal-related kinase (ERK) phosphorylation and activation; treatment with JNK and ERK inhibitors markedly reduced PUMA, Bax, Fas, and DR4 levels and reduced apoptosis but not ROS generation. Furthermore, antioxidants attenuated ar-turmerone-mediated ROS production; mitochondrial dysfunction; JNK and ERK activation; PUMA, Bax, Fas, and DR4 expression; and apoptosis. Taken together, these results suggest that ar-turmerone-induced apoptosis in HepG2 cells is through ROS-mediated activation of ERK and JNK kinases and triggers both intrinsic and extrinsic caspase activation, leading to apoptosis. On the basis of these observations, ar-turmerone deserves further investigation as a natural anticancer and cancer-preventive agent.

Original languageEnglish
Pages (from-to)9620-9630
Number of pages11
JournalJournal of Agricultural and Food Chemistry
Volume60
Issue number38
DOIs
Publication statusPublished - Sep 26 2012
Externally publishedYes

Fingerprint

Curcuma
Curcuma longa
Hep G2 Cells
hepatoma
Carbon Dioxide
aromatic compounds
reactive oxygen species
Hepatocellular Carcinoma
Reactive Oxygen Species
apoptosis
carbon dioxide
phosphotransferases (kinases)
Phosphotransferases
Apoptosis
TNF-Related Apoptosis-Inducing Ligand Receptors
CD95 Antigens
Chemical activation
cells
Modulators
caspases

Keywords

  • apoptosis
  • ar-turmerone
  • Curcuma
  • hepatocellular carcinoma cells
  • reactive oxygen species

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Chemistry(all)

Cite this

Supercritical carbon dioxide extraction of aromatic turmerone from Curcuma longa Linn. Induces apoptosis through reactive oxygen species-triggered intrinsic and extrinsic pathways in human hepatocellular carcinoma HepG2 cells. / Cheng, Shao Bin; Wu, Li Chen; Hsieh, Yun Chih; Wu, Chi Hao; Chan, Yu Ju; Chang, Li Hsun; Chang, Chieh Ming J; Hsu, Shih Lan; Teng, Chieh Lin; Wu, Chun Chi.

In: Journal of Agricultural and Food Chemistry, Vol. 60, No. 38, 26.09.2012, p. 9620-9630.

Research output: Contribution to journalArticle

Cheng, Shao Bin ; Wu, Li Chen ; Hsieh, Yun Chih ; Wu, Chi Hao ; Chan, Yu Ju ; Chang, Li Hsun ; Chang, Chieh Ming J ; Hsu, Shih Lan ; Teng, Chieh Lin ; Wu, Chun Chi. / Supercritical carbon dioxide extraction of aromatic turmerone from Curcuma longa Linn. Induces apoptosis through reactive oxygen species-triggered intrinsic and extrinsic pathways in human hepatocellular carcinoma HepG2 cells. In: Journal of Agricultural and Food Chemistry. 2012 ; Vol. 60, No. 38. pp. 9620-9630.
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abstract = "The mechanisms underlying the antiproliferative and antitumor activities of aromatic turmerone (ar-turmerone), a volatile turmeric oil isolated from Curcuma longa Linn., have been largely unknown. In this study, 86{\%} pure ar-turmerone was extracted by supercritical carbon dioxide and liquid-solid chromatography and its potential effects and molecular mechanisms on cell proliferation studied in human hepatocellular carcinoma cell lines. Ar-turmerone exhibited significant antiproliferative activity, with 50{\%} inhibitory concentrations of 64.8 ± 7.1, 102.5 ± 11.5, and 122.2 ± 7.6 μg/mL against HepG2, Huh-7, and Hep3B cells, respectively. Ar-turmerone-induced apoptosis, confirmed by increased annexin V binding and DNA fragmentation, was accompanied by reactive oxygen species (ROS) production, mitochondrial membrane potential dissipation, increased Bax and p53 up-regulated modulator of apoptosis (PUMA) levels, Bax mitochondrial translocation, cytochrome c release, Fas and death receptor 4 (DR4) augmentation, and caspase-3, -8, and -9 activation. Exposure to caspase inhibitors, Fas-antagonistic antibody, DR4 antagonist, and furosemide (a blocker of Bax translocation) effectively abolished ar-turmerone-triggered apoptosis. Moreover, ar-turmerone stimulated c-Jun N-terminal kinase (JNK) and extracellular signal-related kinase (ERK) phosphorylation and activation; treatment with JNK and ERK inhibitors markedly reduced PUMA, Bax, Fas, and DR4 levels and reduced apoptosis but not ROS generation. Furthermore, antioxidants attenuated ar-turmerone-mediated ROS production; mitochondrial dysfunction; JNK and ERK activation; PUMA, Bax, Fas, and DR4 expression; and apoptosis. Taken together, these results suggest that ar-turmerone-induced apoptosis in HepG2 cells is through ROS-mediated activation of ERK and JNK kinases and triggers both intrinsic and extrinsic caspase activation, leading to apoptosis. On the basis of these observations, ar-turmerone deserves further investigation as a natural anticancer and cancer-preventive agent.",
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AU - Wu, Li Chen

AU - Hsieh, Yun Chih

AU - Wu, Chi Hao

AU - Chan, Yu Ju

AU - Chang, Li Hsun

AU - Chang, Chieh Ming J

AU - Hsu, Shih Lan

AU - Teng, Chieh Lin

AU - Wu, Chun Chi

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AB - The mechanisms underlying the antiproliferative and antitumor activities of aromatic turmerone (ar-turmerone), a volatile turmeric oil isolated from Curcuma longa Linn., have been largely unknown. In this study, 86% pure ar-turmerone was extracted by supercritical carbon dioxide and liquid-solid chromatography and its potential effects and molecular mechanisms on cell proliferation studied in human hepatocellular carcinoma cell lines. Ar-turmerone exhibited significant antiproliferative activity, with 50% inhibitory concentrations of 64.8 ± 7.1, 102.5 ± 11.5, and 122.2 ± 7.6 μg/mL against HepG2, Huh-7, and Hep3B cells, respectively. Ar-turmerone-induced apoptosis, confirmed by increased annexin V binding and DNA fragmentation, was accompanied by reactive oxygen species (ROS) production, mitochondrial membrane potential dissipation, increased Bax and p53 up-regulated modulator of apoptosis (PUMA) levels, Bax mitochondrial translocation, cytochrome c release, Fas and death receptor 4 (DR4) augmentation, and caspase-3, -8, and -9 activation. Exposure to caspase inhibitors, Fas-antagonistic antibody, DR4 antagonist, and furosemide (a blocker of Bax translocation) effectively abolished ar-turmerone-triggered apoptosis. Moreover, ar-turmerone stimulated c-Jun N-terminal kinase (JNK) and extracellular signal-related kinase (ERK) phosphorylation and activation; treatment with JNK and ERK inhibitors markedly reduced PUMA, Bax, Fas, and DR4 levels and reduced apoptosis but not ROS generation. Furthermore, antioxidants attenuated ar-turmerone-mediated ROS production; mitochondrial dysfunction; JNK and ERK activation; PUMA, Bax, Fas, and DR4 expression; and apoptosis. Taken together, these results suggest that ar-turmerone-induced apoptosis in HepG2 cells is through ROS-mediated activation of ERK and JNK kinases and triggers both intrinsic and extrinsic caspase activation, leading to apoptosis. On the basis of these observations, ar-turmerone deserves further investigation as a natural anticancer and cancer-preventive agent.

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