title: Hedgehog targeting by cyclopamine suppresses head and neck squamous cell carcinoma and enhances chemotherapeutic effects.
abstract: BACKGROUND
  The hedgehog signaling pathway (HH) is involved in tumorigenesis in a variety of human malignancies. In head and neck squamous cell carcinomas (HNSCC), Hh overexpression was associated with poor prognosis. Therefore, we analyzed the effect of Hh signaling blockade with cyclopamine on colony formation of cells from HNSCC samples.
  
  
  METHODS
  HNSCC biopsies were cultured alone for reference or with serial dilutions of cyclopamine (5-5,000 nM), docetaxel (137.5-550 nM), or cisplatin (1,667-6,667 nM) and their binary combinations. Cytokeratin-positive colonies were counted after fluorescent staining.
  
  
  RESULTS
  Cyclopamine concentration-dependently inhibited HNSCC ex vivo [(IC50) at about 500 nM]. In binary combinations, cyclopamine additively enhanced the suppressive effects of cisplatin and docetaxel on HNSCC colony formation.
  
  
  CONCLUSIONS
  Our findings define SMO--a Hh component- as a potential target in HNSCC and suggest the utility of Hh targeting in future multimodal treatment regimens for HNSCC.
authors.affiliation: Department of Otolaryngology, University of Leipzig, Leipzig, Germany. christian.mozet@medizin.uni-leipzig.de
authors.forename: Christian
authors.initials: C
authors.lastname: Mozet
authors.forename: Matthaeus
authors.initials: M
authors.lastname: Stoehr
authors.forename: Kamelia
authors.initials: K
authors.lastname: Dimitrova
authors.forename: Andreas
authors.initials: A
authors.lastname: Dietz
authors.forename: Gunnar
authors.initials: G
authors.lastname: Wichmann
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D000077143:Docetaxel; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007624:KB Cells; D007633:Keratins / Q000096:biosynthesis; D008297:Male; D058990:Molecular Targeted Therapy; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D014704:Veratrum Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D043823:Taxoids; D014704:Veratrum Alkaloids; D000077143:Docetaxel; D007633:Keratins; D002945:Cisplatin; C000541:cyclopamine
keywords: Head and neck squamous cell carcinoma (HNSCC); cisplatin; cyclopamine; docetaxel; hedgehog pathway; synergism