Sorafenib alone or as combination therapy for growth control of cholangiocarcinoma

Background/aim: Treatment options of advanced cholangiocarcinoma (CC) are unsatisfactory and new therapeutic approaches are mandatory. Dysregulations of the mitogen-activated kinase (MAPK) pathway associated with proliferative advantages of tumors are commonly observed in CCs. The novel multi-kinase inhibitor sorafenib potently suppresses the growth of various cancers by inhibiting kinases of Wild-type B-Raf, mutant(V559E)B-Raf and C-Raf but its effects on CC remains to be explored. We therefore studied the antineoplastic potency of sorafenib in human CC cells alone and in combination with conventional cytostatics or IGF-1R inhibition. Methods and results: Sorafenib treatment dose-dependently blocked growth- factor-induced activation of the MAPKP and inhibited the proliferation of EGI-1 and TFK-1 CC cells in a time-and dose-dependent manner. At least two mechanisms accounted for the effects observed: arrest at the G(1)/G(0)- transition of the cell cycle and induction of apoptosis. The cell cycle arrest was associated with upregulation of the cyclin-dependent kinase inhibitor p27(Kip1) and down-regulation of cyclin D1. Combining sorafenib with doxoruibicin or IGF-1R-inhibition resulted in (over)additive antiproliferative effects whereas co-application of sorafenib and the antimetabolites 5-FU or gemcitabine diminished the antineoplastic effects of the cytostatics. Conclusion: Our study demonstrates that the growth of human CC cells can be potently suppressed by sorafenib alone or in certain combination therapies and may provide a promising rationale for future in vivo evaluations and clinical trials. (c) 2007 Elsevier Inc. All rights reserved.