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Growth inhibition of human cholangiocarcinoma by sorafenib‐based mono‐ and combination treatment
Author(s) -
Höpfner Michael,
Baradari Viola,
Huether Alexander,
Scherübl Hans
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1136.9
Subject(s) - sorafenib , downregulation and upregulation , mapk/erk pathway , cancer research , cell growth , cyclin dependent kinase , cyclin d1 , pharmacology , apoptosis , growth inhibition , cell cycle checkpoint , in vivo , cell cycle , chemistry , cancer , kinase , medicine , biology , hepatocellular carcinoma , biochemistry , microbiology and biotechnology , gene
Background: Treatment options of advanced cholangiocarcinoma (CC) are unsatisfactory and new therapeutic approaches are mandatory. The Ras/Raf/MAPK‐pathway is one of the most significant cellular signaling sequences in the development and maintenance of cancer. Thus inhibition of this key signaling pathway appears to be a promising approach for novel CC‐treatment. Here we investigated the antineoplastic effects of sorafenib (Sor), a novel multi‐kinase inhibitor which potently suppresses wild‐type‐ and mutated Raf‐isoforms. Sor has already shown antineoplastic efficacy in some cancer types but its suitability for treatment of CC has not been investigated so far. Results: Sor dose‐dependently blocked growth‐factor‐induced MAPK‐activity and inhibited the proliferation CC cells in a time and dose‐dependent manner. At least two mechanisms accounted for the effects observed: G1/G0‐ arrest of the cell cycle and apoptosis. G1/G0‐arrest was associated with upregulation of the cdk‐inhibitor p27 and downregulation of cyclin D1. Combining Sor with doxorubicin, the HDAC inhibitor MS‐275 or IGF‐1R‐inhibition resulted in (over‐) addititve antiproliferative effects. Conclusion: Our study demonstrates that the growth of human CC cells can be potently suppressed by Sor alone or in certain combination therapies and may provide a promising rationale for future in vivo evaluations and clinical trials.