Potent in vitro and in vivo antitumor activity of sorafenib against human intrahepatic cholangiocarcinoma cells

Abstract

Intrahepatic cholangiocarcinoma (ICC) is rising in clinical importance due to the increasing incidence worldwide, poor prognosis, and suboptimal response to therapies. New effective therapeutic approaches are needed for improvement of treatment outcome. A recent study showed that sorafenib, a multikinase inhibitor that acts predominantly through inhibition of Raf kinase and vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, exhibited potent antitumor activity in a preclinical model of cholangiocarcinoma cells. We tested the in vitro and in vivo antitumor activity of sorafenib against human ICC cell lines. Treatment of ICC cells with sorafenib resulted in inhibition of proliferation and induction of apoptosis in the cell lines. In the cells treated with sorafenib, phosphorylation of mitogen-activated protein kinase kinase (MEK) and mitogen-activated protein kinase (MAPK) and also interleukin-6-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) were inhibited in a dose-dependent manner. Down-regulation of the anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) paralleled the reduced phosphorylation of STAT3. However, sorafenib induced no significant change in the cell cycle distribution and the expression levels of cyclin D1 and p27(Kip1) in the cells. For the in vivo antitumor activity, oral administration of sorafenib significantly inhibited the growth of subcutaneous tumors established in immunodeficient mice at doses of 10, 30, and 100 mg/kg. Moreover, administration of sorafenib (30 mg/kg) to animals with peritoneally disseminated ICC resulted in significantly prolonged survival compared with that of untreated animals (76 vs. 43 days in treated and vehicle-treated mice, respectively). These results indicate that sorafenib is a potent agent that may provide a new therapeutic option for human ICC.