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Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

Kiesslich, T; Mayr, C; Wachter, J; Bach, D; Fuereder, J; Wagner, A; Alinger, B; Pichler, M; Di Fazio, P; Ocker, M; Berr, F; Neureiter, D.
Activated hedgehog pathway is a potential target for pharmacological intervention in biliary tract cancer.
Mol Cell Biochem. 2014; 396(1-2):257-268
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Autor/innen der Med Uni Graz:
Pichler Martin
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Abstract:
Hedgehog (Hh) signalling contributes to carcinogenesis and represents a valid druggable target in human cancers, possibly also in biliary tract cancer (BTC). We analysed the expression of Hh components in BTC using eight heterogeneously differentiated cell lines, xenograft tumours and a human tissue microarray. The dose-, time- and cell line-dependent effects of two Hh inhibitors (cyclopamine and Gant-61) were analysed in vitro for survival, apoptosis, cell cycle distribution and possible synergism with conventional chemotherapeutic agents. In human BTC samples, the sonic Hh ligand and the Gli1 transcription factor showed increased expression in tumours compared to normal adjacent tissue and were significantly associated with high tumour grade and positive lymph node status. In BTC cell lines, we could confirm the Hh component expression at varying extent within the employed cell lines in vitro and in vivo indicating non-canonical signalling. Both Hh inhibitors showed dose-dependent cytotoxicity above 5 µM with a stronger effect for Gant-61 inducing apoptosis whereas cyclopamine rather inhibited proliferation. Cytotoxicity was associated with low cytokeratin expression and higher mesenchymal marker expression such as vimentin. Additionally, drug combinations of Gant-61 with conventional chemotherapy (cisplatin) exerted synergistic effects. In conclusion, Hh pathway is significantly activated in human BTC tissue compared to normal adjacent tissue. The current data demonstrate for the first time an effective anticancer activity of especially Gant-61 in BTC and suggest second generation Hh pathway inhibitors as a potential novel treatment strategy in BTC.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Antineoplastic Agents - pharmacology
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Apoptosis - drug effects
Biliary Tract Neoplasms - drug therapy
Biliary Tract Neoplasms - metabolism
Biliary Tract Neoplasms - pathology
Cell Line, Tumor - drug effects
Cisplatin - administration & dosage
Dose-Response Relationship, Drug -
Hedgehog Proteins - antagonists & inhibitors
Hedgehog Proteins - genetics
Hedgehog Proteins - metabolism
Humans -
Mice, Mutant Strains -
Molecular Targeted Therapy - methods
Pyridines - administration & dosage
Pyridines - pharmacology
Pyrimidines - administration & dosage
Pyrimidines - pharmacology
Signal Transduction - drug effects
Tissue Array Analysis -
Transcription Factors - metabolism
Veratrum Alkaloids - pharmacology
Xenograft Model Antitumor Assays -
Zinc Finger Protein GLI1 -

Find related publications in this database (Keywords)
Biliary tract cancer
Hedgehog
Oncogenic signalling
Pharmacological inhibition
Cyclopamine
Gant-61
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