Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
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
Doi: 10.1007/s11010-014-2161-9
Web of Science
PubMed
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- Co-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