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Phenethyl isothiocyanate induces apoptosis of cholangiocarcinoma cells through interruption of glutathione and mitochondrial pathway

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An Erratum to this article was published on 12 September 2013

Abstract

Phenethyl isothiocyanate (PEITC) is a natural isothiocyanate with anticancer activity against many drug-resistant cancer cells. A body of evidence suggests that PEITC enhances oxidative stress leading to cancer cell death. Cholangiocarcinoma (CCA) is an aggressive bile duct cancer with resistance to chemotherapeutic drugs. PEITC rapidly kills KKU-100 CCA cells with concurrent induction of cellular glutathione depletion, superoxide formation, and loss of mitochondrial transmembrane potential. The loss was associated with increased Bax and decreased Bcl-xl proteins followed by the release of cytochrome c and the activation of caspase-9 and -3. Although TEMPOL could prevent superoxide formation, it did not prevent the disruption of glutathione (GSH) redox, mitochondrial dysfunction, and cell death. On the other hand, N-acetylcysteine could prevent the events and cell death. It was concluded that disruption of GSH redox but not superoxide formation may be an initial step leading to mitochondrial injury. PEITC could be a promising chemopreventive agent for CCA.

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Abbreviations

BSO:

Buthionine sulfoximine

TEMPOL:

4-hydroxy-TEMPO

CCA:

Cholangiocarcinoma

PEITC:

Phenethyl isothiocyanate

GSH:

Glutathione

GSSG:

Glutathione disulfide

∆Ψ m :

Mitochondrial transmembrane potential

NAC:

N-acetyl-L-cysteine

ROS:

Reactive oxygen species

SRB:

Sulforhodamine B

JC-1:

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

MOMP:

Mitochondrial outer membrane permeabilization

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Acknowledgments

This work was supported by the Thailand Research Fund (BRG5480011), the Office of the Higher Education Commission through SHeP-GMS of Khon Kaen University, grant-in-aid from Faculty of Medicine, Khon Kaen University, and a scholarship from the Office of the Higher Education Commission to Ornanong Tusskorn. Valuable suggestions on the manuscript of Prof. Yukifumi Nawa of Faculty of Medicine, Khon Kaen University are gratefully acknowledged.

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand, 40002

    Ornanong Tusskorn, Auemduan Prawan, Laddawan Senggunprai & Veerapol Kukongviriyapan

  2. Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, Thailand

    Auemduan Prawan, Laddawan Senggunprai & Veerapol Kukongviriyapan

  3. Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

    Upa Kukongviriyapan

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  1. Ornanong Tusskorn
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  2. Auemduan Prawan
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  3. Laddawan Senggunprai
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  4. Upa Kukongviriyapan
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  5. Veerapol Kukongviriyapan
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Correspondence to Veerapol Kukongviriyapan.

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Tusskorn, O., Prawan, A., Senggunprai, L. et al. Phenethyl isothiocyanate induces apoptosis of cholangiocarcinoma cells through interruption of glutathione and mitochondrial pathway. Naunyn-Schmiedeberg's Arch Pharmacol 386, 1009–1016 (2013). https://doi.org/10.1007/s00210-013-0906-8

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  • DOI: https://doi.org/10.1007/s00210-013-0906-8

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