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Methyl antcinate A from Antrodia camphorata induces apoptosis in human liver cancer cells through oxidant-mediated cofilin- and Bax-triggered mitochondrial pathway.
Chem Res Toxicol. 2010 Jul 19; 23(7):1256-67.CR

Abstract

We investigated the effects of antcin A, antcin C, and methyl antcinate A (MAA) isolated from Antrodia camphorata on the proliferation of human liver cancer cell lines Huh7, HepG2, and Hep3B and the normal cell rat hepatocytes. The three compounds selectively inhibit the proliferation of tumor cells rather than normal cells, with IC(50) values ranging from 30.2 to 286.4 microM. The compound MAA was a more potent cytotoxic agent than antcins A and C with IC(50) values of 52.2, 78.0, and 30.2 microM against HepG2, Hep3B, and Huh7 cells, respectively. To elucidate the molecular mechanism, treatment of Huh7 cells with 100 microM MAA induced an apoptotic cell death, which was characterized by the appearance of sub-G1 population, DNA fragmentation, TUNEL positive cells, and caspase activation. MAA triggered the mitochondrial apoptotic pathway, as indicated by an increase in the protein expression of Bax, Bak, and PUMA, as well as a decrease in Bcl-(XL) and Bcl-2 and disruption of mitochondrial membrane potential and promotion of mitochondrial cytochrome c release, as well as activation of caspases-2, -3, and -9. We also found that pretreatment with inhibitors of caspases-2, -3, and -9 noticeably blocked MAA-triggered apoptosis. Furthermore, intracellular reactive oxygen species (ROS) generation and NADPH oxidase activation were observed in MAA-stimulated Huh7 cells. Mechanistic studies showed that MAA induces mitochondrial translocation of cofilin. When Huh7 cells were treated with cyclosporine A and bongkrekic acid, an inhibitor of the mitochondria permeability transition pore, the levels of cell death induced by MAA were significantly attenuated. Additionally, pretreatment of Huh7 cells with antioxidants ascorbic acid and N-acetyl cysteine markedly attenuated the MAA-induced apoptosis by upregulation of Bax, Bak, and PUMA, mitochondrial translocation of cofilin, activation of caspase-3, and cell death. Taken together, our results provide the first evidence of the activation of the ROS-dependent cofilin- and Bax-triggered mitochondrial pathway as a critical mechanism of MAA-induced cell death in liver cancer cells.

Authors+Show Affiliations

Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan, Republic of China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20557081

Citation

Hsieh, Yun-Chih, et al. "Methyl Antcinate a From Antrodia Camphorata Induces Apoptosis in Human Liver Cancer Cells Through Oxidant-mediated Cofilin- and Bax-triggered Mitochondrial Pathway." Chemical Research in Toxicology, vol. 23, no. 7, 2010, pp. 1256-67.
Hsieh YC, Rao YK, Wu CC, et al. Methyl antcinate A from Antrodia camphorata induces apoptosis in human liver cancer cells through oxidant-mediated cofilin- and Bax-triggered mitochondrial pathway. Chem Res Toxicol. 2010;23(7):1256-67.
Hsieh, Y. C., Rao, Y. K., Wu, C. C., Huang, C. Y., Geethangili, M., Hsu, S. L., & Tzeng, Y. M. (2010). Methyl antcinate A from Antrodia camphorata induces apoptosis in human liver cancer cells through oxidant-mediated cofilin- and Bax-triggered mitochondrial pathway. Chemical Research in Toxicology, 23(7), 1256-67. https://doi.org/10.1021/tx100116a
Hsieh YC, et al. Methyl Antcinate a From Antrodia Camphorata Induces Apoptosis in Human Liver Cancer Cells Through Oxidant-mediated Cofilin- and Bax-triggered Mitochondrial Pathway. Chem Res Toxicol. 2010 Jul 19;23(7):1256-67. PubMed PMID: 20557081.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Methyl antcinate A from Antrodia camphorata induces apoptosis in human liver cancer cells through oxidant-mediated cofilin- and Bax-triggered mitochondrial pathway. AU - Hsieh,Yun-Chih, AU - Rao,Yerra Koteswara, AU - Wu,Chun-Chi, AU - Huang,Chi-Ying F, AU - Geethangili,Madamanchi, AU - Hsu,Shih-Lan, AU - Tzeng,Yew-Min, PY - 2010/6/19/entrez PY - 2010/6/19/pubmed PY - 2010/12/14/medline SP - 1256 EP - 67 JF - Chemical research in toxicology JO - Chem. Res. Toxicol. VL - 23 IS - 7 N2 - We investigated the effects of antcin A, antcin C, and methyl antcinate A (MAA) isolated from Antrodia camphorata on the proliferation of human liver cancer cell lines Huh7, HepG2, and Hep3B and the normal cell rat hepatocytes. The three compounds selectively inhibit the proliferation of tumor cells rather than normal cells, with IC(50) values ranging from 30.2 to 286.4 microM. The compound MAA was a more potent cytotoxic agent than antcins A and C with IC(50) values of 52.2, 78.0, and 30.2 microM against HepG2, Hep3B, and Huh7 cells, respectively. To elucidate the molecular mechanism, treatment of Huh7 cells with 100 microM MAA induced an apoptotic cell death, which was characterized by the appearance of sub-G1 population, DNA fragmentation, TUNEL positive cells, and caspase activation. MAA triggered the mitochondrial apoptotic pathway, as indicated by an increase in the protein expression of Bax, Bak, and PUMA, as well as a decrease in Bcl-(XL) and Bcl-2 and disruption of mitochondrial membrane potential and promotion of mitochondrial cytochrome c release, as well as activation of caspases-2, -3, and -9. We also found that pretreatment with inhibitors of caspases-2, -3, and -9 noticeably blocked MAA-triggered apoptosis. Furthermore, intracellular reactive oxygen species (ROS) generation and NADPH oxidase activation were observed in MAA-stimulated Huh7 cells. Mechanistic studies showed that MAA induces mitochondrial translocation of cofilin. When Huh7 cells were treated with cyclosporine A and bongkrekic acid, an inhibitor of the mitochondria permeability transition pore, the levels of cell death induced by MAA were significantly attenuated. Additionally, pretreatment of Huh7 cells with antioxidants ascorbic acid and N-acetyl cysteine markedly attenuated the MAA-induced apoptosis by upregulation of Bax, Bak, and PUMA, mitochondrial translocation of cofilin, activation of caspase-3, and cell death. Taken together, our results provide the first evidence of the activation of the ROS-dependent cofilin- and Bax-triggered mitochondrial pathway as a critical mechanism of MAA-induced cell death in liver cancer cells. SN - 1520-5010 UR - https://www.unboundmedicine.com/medline/citation/20557081/Methyl_antcinate_A_from_Antrodia_camphorata_induces_apoptosis_in_human_liver_cancer_cells_through_oxidant_mediated_cofilin__and_Bax_triggered_mitochondrial_pathway_ L2 - https://dx.doi.org/10.1021/tx100116a DB - PRIME DP - Unbound Medicine ER -