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α-Mangostin induces mitochondrial dependent apoptosis in human hepatoma SK-Hep-1 cells through inhibition of p38 MAPK pathway

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Abstract

α-Mangostin is a dietary xanthone that has been shown to have anti-cancer and anti-proliferative properties in various types of human cancer cells. This study investigates the molecular mechanism of the apoptosis-inducing effects of α-mangostin on human hepatocellular carcinoma (HCC) cells. We observed that α-mangostin reduces the viability of HCC cells in a dose- and time-dependent manner. α-Mangostin mediated apoptosis of SK-Hep-1 cells is accompanied by nuclear chromatin condensation and cell cycle arrest in the sub-G1 phases as well as phosphatidylserine exposure. Furthermore, α-mangostin triggered the mitochondrial caspase apoptotic pathway, as indicated by the loss of mitochondrial membrane potential, the release of cytochrome c from mitochondria, and the regulation of B cell lymphoma 2 family member expression. Moreover, α-mangostin inhibited a sustained activation of p38 mitogen-activated protein kinase (MAPK) phosphorylation, and treatment with a p38 MAPK inhibitor enhanced α-mangostin-induced caspase activation and apoptosis in SK-Hep-1 cells. In vivo xenograft mice experiments revealed that α-mangostin significantly reduced tumor growth and weight in mice inoculated with SK-Hep-1 cells. These findings demonstrate that α-mangostin induces mitochondria-mediated apoptosis through inactivation of the p38 MAPK signaling pathway and that α-mangostin inhibits the in vivo tumor growth of SK-Hep-1 xenograft mice.

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Abbreviations

HCC:

Human hepatocellular carcinoma

MMP:

Mitochondrial membrane potential

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide

JC-1:

5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethylbenzimidazol-carbocyanine iodide

MAPK:

Mitogen-activated protein kinase

FBS:

Fetal bovine serum

PI:

Propidium iodide

PARP:

Poly(ADP-ribose) polymerase

Bcl-2:

B cell lymphoma 2

Bax:

B cell lymphoma 2-associated X protein

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Acknowledgments

This work was supported by Grants from National Science Council, Taiwan (NSC100-2313-B-040-001 and NSC101-2313-B-040-001) and Chung Shan Medical Hospital, Taichung, Taiwan (CSH-2011-C-026).

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC

    Shu-Ching Hsieh & Shun-Fa Yang

  2. Department of Rehabilitation Science, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli County, Taiwan, ROC

    Min-Hsien Huang

  3. Department of Acupressure Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli County, Taiwan, ROC

    Min-Hsien Huang

  4. Institute of Biochemistry and Biotechnology, College of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC

    Chun-Wen Cheng, Jyun-Hao Hung & Yi-Hsien Hsieh

  5. Department of Medical Research, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan, ROC

    Shun-Fa Yang

  6. Chung Shan Medical University Clinical Laboratory, Department of Biochemistry, School of Medicine, Chung Shan Medical University Hospital, No. 110, Section 1, Chien-Kuo N. Road, Taichung, Taiwan, ROC

    Yi-Hsien Hsieh

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  1. Shu-Ching Hsieh
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Corresponding authors

Correspondence to Shun-Fa Yang or Yi-Hsien Hsieh.

Additional information

Shun-Fa Yang and Yi-Hsien Hsieh contributed equally to this work.

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Hsieh, SC., Huang, MH., Cheng, CW. et al. α-Mangostin induces mitochondrial dependent apoptosis in human hepatoma SK-Hep-1 cells through inhibition of p38 MAPK pathway. Apoptosis 18, 1548–1560 (2013). https://doi.org/10.1007/s10495-013-0888-5

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  • DOI: https://doi.org/10.1007/s10495-013-0888-5

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