Imatinib mesylate induces apoptosis in human cholangiocarcinoma cells.
BACKGROUND
Cholangiocarcinoma is a highly malignant, usually fatal cancer with limited therapeutic options. Receptor tyrosine kinases contribute to the development and progression of this cancer. The relatively selective tyrosine kinase inhibitor imatinib mesylate (STI-571 or Gleevec(R)) has recently been licensed. However, the ability of this drug to inhibit signal transduction and induce apoptosis in human cholangiocarcinoma cells is incompletely studied. Thus, our goal was to examine the ability of STI-571 to induce apoptosis in KMCH-1 cells, a human cholangiocarcinoma cell line.


METHODS
Apoptosis was assessed morphologically and also biochemically by measuring caspase activity and the mitochondrial membrane potential. STI-571 induced apoptosis and inhibited growth of KMCH-1 cells in a time- and concentration-dependent manner. The induction of apoptosis was accompanied by mitochondrial depolarization followed by a 4.5-fold increase in caspase activation and was abrogated by the pancaspase inhibitor z-VAD(OMe)-fmk. Interestingly, cholangiocarcinoma cells do not express detectable PDGFR, c-Abl or c-Kit, which are protein kinases known to be directly inhibited by STI-571. However, a significant decrease in epidermal growth factor receptor (EGFR) and focal adhesion kinase (FAK) phosphorylation was observed following treatment with STI-571. This decrease in EGFR and FAK phosphorylation was associated with a reduction in Akt activity resulting in loss of Mcl-1, a potent anti-apoptotic Bcl-2 family protein.


CONCLUSIONS
These results indicate that STI-571 induces caspase-dependent apoptosis in a human cholangiocarcinoma cell line and suggest that STI-571 might warrant further investigation as a possible agent for treatment of human cholangiocarcinoma.
Chiorean
Mihnea V
MV
Division of Gastroenterology and Hepatology, and Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, MN, USA.
Guicciardi
Maria Eugenia
ME
Yoon
Jung-Hwan
JH
Bronk
Steven F
SF
Kaufmanns
Scott H
SH
Gores
Gregory J
GJ
D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D001650:Bile Duct Neoplasms / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic; D020169:Caspases / Q000187:drug effects* / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000473:pathology*; D004815:Epidermal Growth Factor / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011336:Probability; D011743:Pyrimidines / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D004815:Epidermal Growth Factor; D000068877:Imatinib Mesylate; D020169:Caspases