Abstract
BackgroundPhenethyl isothiocyanate (PEITC) is a cancer chemopreventive agent from cruciferous vegetables. Cholangiocarcinoma (CCA) is a chemo-resistant cancer with very poor prognosis. We evaluated the effects of PEITC on induction of apoptotic cell death in relation to cellular glutathione (GSH) and mitochondrial function of a CCA cell line, KKU-M214.MethodsCytotoxic effects of PEITC on a CCA cell line, KKU-M214, and a reference cell line, Chang cells were evaluated. To delineate mechanisms of cell death, the following parameters were measured; GSH and superoxide levels as the oxidative status parameters, apoptosis related proteins levels using Western blotting. Cellular free calcium level and mitochondrial transmembrane potential were also measured.ResultsPEITC induced apoptotic cell death of both KKU-M214 and Chang cells. After PEITC treatment, both cells showed decrease of Bcl-xl and increase of Bax levels. While KKU-M214 cells released AIF, Chang cells released cytochrome c, with subsequent activation of caspase 3 and 9, upon PEITC treatment. PEITC induced superoxide formation in both cells, although it seemed not play a role in cell death. PEITC caused GSH redox stress in different ways in two cell types, because N-acetylcysteine (NAC) prevented redox stress in Chang but not in KKU-M214 cells. The loss of mitochondrial transmembrane potential was induced by PEITC concurrent with GSH stress, but was not a primary cause of cell death. The rapid increase of free calcium level in cytosol was associated with cell death in both cell lines. These events were prevented by NAC in Chang cells, but not in KKU-M214 cells.ConclusionPEITC induced cell death KKU-M214 cells and Chang cells via increase of cellular calcium mobilization and activation of mitochondrial cell death pathway. The effects of PEITC on the redox stress was mediated via different ways in CCA and Chang cells because NAC could prevent redox stress in Chang cells, but not in KKU-M214 cells. The multiple effects of PEITC may be useful for the development of novel chemotherapy for CCA.
Highlights
Phenethyl isothiocyanate (PEITC) is a cancer chemopreventive agent from cruciferous vegetables
For the better understanding of the anticancer mechanisms of PEITC, we evaluated the effects of PEITC on a bile duct cancer cell line, KKU-M214 in relation to GSH redox stress and mitochondrial function
While caspase-3 and −9 activities in KKU-M214 cells were unchanged after PEITC treatment, they were significantly increased in PEITCtreated Chang cells (Figure 3C-F)
Summary
Phenethyl isothiocyanate (PEITC) is a cancer chemopreventive agent from cruciferous vegetables. Cholangiocarcinoma (CCA) is a chemo-resistant cancer with very poor prognosis. Cholangiocarcinoma (CCA) is a malignancy originating from the bile ducts, usually adenocarcinomatous, and is the second common primary liver cancer [1]. CCA is a rare cancer worldwide, but the most common form of liver cancer in Mekong subregion countries, including northeastern Thailand, Cambodia, Vietnam and Laos [2]. Most of CCA patients are already in the advanced stage at diagnosis, and the radical surgery is not feasible. Chemotherapy and radiotherapy could not improve the survival of patients with unresectable CCA [3]. Despite of recent advances in chemotherapy for many cancers, management of CCA with chemotherapeutic drugs and biologic agents has so far been unsatisfied. The development of appropriate new chemotherapeutic drugs and new approaches for the treatment of chemo-resistant cancer like CCA should be of the high priority
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