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Suppression of glutathione S-transferases potentiates the cytotoxic effect of phenethyl isothiocyanate in cholangiocarcinoma cells

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Abstract

Phenethyl isothiocyanate (PEITC) is a potential cancer prevention agent that is found in cruciferous vegetables. Previous studies have shown that the effect of PEITC-induced cell death declines rapidly after administration. The metabolic fate of PEITC is modulated by glutathione S-transferases (GST). In this study, we investigated whether GST activity modulates PEITC-induced cytotoxicity on cholangiocarcinoma (CCA) cells. The sensitivity of KKU-M214 and KKU-100 cells to PEITC was associated with GST activity. Two GST inhibitors, ethacrynic acid (EA) and cibacron blue, potentiated the cytotoxic effect of PEITC in CCA cells. PEITC-induced glutathione (GSH) depletion and redox stress, whereas EA itself or in combination with PEITC did not alter GSH redox status. The enhanced cytotoxic effect of EA may be due to inhibition of GST activity. This idea was validated by using siRNA directed against GSTP1 mRNA in KKU-M214 cells, and GSTP1 and GSTT1 mRNA in KKU-100 cells. These GST isoforms were abundantly expressed in the cell lines. Knockdown of GSTs in CCA cell lines potentiated the cytotoxic effect of PEITC. The present study shows that the antitumor effect of PEITC was potentiated by the suppression of GST activity. The inhibition of GST could be a crucial strategy to potentiate chemotherapeutic effect of PEITC on CCA.

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Abbreviations

CCA:

Cholangiocarcinoma

PEITC:

Phenethyl isothiocyanate

GSH:

Glutathione

GSSG:

Glutathione disulfide

GSTs:

Glutathione S-transferases

SRB:

Sulphorhodamine B

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Acknowledgements

We would like to acknowledge Dr. Justin Thomas Reese for editing the manuscript via Publication Clinic KKU.

Funding

This work was supported by grant-in-aid from Khon Kaen University and National Research Council of Thailand, Cholangiocarcinoma Research Institute, Khon Kaen University.

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Authors and Affiliations

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

    Ornanong Tusskorn, Tueanjai Khunluck, Auemduan Prawan, Laddawan Senggunprai & Veerapol Kukongviriyapan

  2. Chulabhorn International College of Medicine, Thammasat University, Khlong Luang, Pathum Thani, 12120, Thailand

    Ornanong Tusskorn

  3. Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand

    Auemduan Prawan, Laddawan Senggunprai & Veerapol Kukongviriyapan

  4. Department of Physiology Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Upa Kukongviriyapan

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  1. Ornanong Tusskorn
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  2. Tueanjai Khunluck
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Correspondence to Veerapol Kukongviriyapan.

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Tusskorn, O., Khunluck, T., Prawan, A. et al. Suppression of glutathione S-transferases potentiates the cytotoxic effect of phenethyl isothiocyanate in cholangiocarcinoma cells. Naunyn-Schmiedeberg's Arch Pharmacol 391, 657–667 (2018). https://doi.org/10.1007/s00210-018-1492-6

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  • DOI: https://doi.org/10.1007/s00210-018-1492-6

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