Phenethyl isothiocyanate induces apoptosis of cholangiocarcinoma cells through interruption of glutathione and mitochondrial pathway.
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.
Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand, 40002.
Ornanong
O
Tusskorn
Auemduan
A
Prawan
Laddawan
L
Senggunprai
Upa
U
Kukongviriyapan
Veerapol
V
Kukongviriyapan
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D001653:Bile Ducts, Intrahepatic; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D017879:Isothiocyanates; D017382:Reactive Oxygen Species; C058305:phenethyl isothiocyanate; D020169:Caspases; D005978:Glutathione