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

  • Ornanong Tusskorn
  • Tueanjai Khunluck
  • Auemduan Prawan
  • Laddawan Senggunprai
  • Upa Kukongviriyapan
  • Veerapol Kukongviriyapan
Original Article

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.

Keywords

Phenethylisothiocyanate Chemoprevention Cholangiocarcinoma Glutathione S-transferases 

Abbreviations

CCA

Cholangiocarcinoma

PEITC

Phenethyl isothiocyanate

GSH

Glutathione

GSSG

Glutathione disulfide

GSTs

Glutathione S-transferases

SRB

Sulphorhodamine B

Notes

Acknowledgements

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

Funding information

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

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ornanong Tusskorn
    • 1
    • 2
  • Tueanjai Khunluck
    • 1
  • Auemduan Prawan
    • 1
    • 3
  • Laddawan Senggunprai
    • 1
    • 3
  • Upa Kukongviriyapan
    • 4
  • Veerapol Kukongviriyapan
    • 1
    • 3
  1. 1.Department of Pharmacology, Faculty of MedicineKhon Kaen UniversityKhon KaenThailand
  2. 2.Chulabhorn International College of MedicineThammasat UniversityKhlong LuangThailand
  3. 3.Cholangiocarcinoma Research InstituteKhon Kaen UniversityKhon KaenThailand
  4. 4.Department of Physiology Faculty of MedicineKhon Kaen UniversityKhon KaenThailand

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