title: Targeting hedgehog signalling by arsenic trioxide reduces cell growth and induces apoptosis in rhabdomyosarcoma.
abstract: Rhabdomyosarcomas (RMS) are soft tissue tumours treated with a combination of surgery and chemotherapy. However, mortality rates remain high in case of recurrences and metastatic disease due to drug resistance and failure to undergo apoptosis. Therefore, innovative approaches targeting specific signalling pathways are urgently needed. We analysed the impact of different hedgehog (Hh) pathway inhibitors on growth and survival of six RMS cell lines using MTS assay, colony formation assay, 3D spheroid cultures, flow cytometry and western blotting. Especially the glioma-associated oncogene family (GLI) inhibitor arsenic trioxide (ATO) effectively reduced viability as well as clonal growth and induced cell death in RMS cell lines of embryonal, alveolar and sclerosing, spindle cell subtype, whereas normal skeletal muscle cells were hardly compromised by ATO. Combination of ATO with itraconazole potentiated the reduction of colony formation and spheroid size. These results show that ATO is a promising substance for treatment of relapsed and refractory RMS by directly targeting GLI transcription factors. The combination with itraconazole or other chemotherapeutic drugs has the opportunity to enforce the treatment efficiency of resistant and recurrent RMS.
authors.affiliation: Laboratory of Cell Biology, Department of Orthopaedic Surgery, Eberhard Karls University Tuebingen, Tuebingen, Germany.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Boehme
authors.affiliation: Laboratory of Cell Biology, Department of Orthopaedic Surgery, Eberhard Karls University Tuebingen, Tuebingen, Germany.
authors.forename: Julian J
authors.initials: JJ
authors.lastname: Zaborski
authors.affiliation: Laboratory of Cell Biology, Department of Orthopaedic Surgery, Eberhard Karls University Tuebingen, Tuebingen, Germany.
authors.forename: Rosa
authors.initials: R
authors.lastname: Riester
authors.affiliation: Laboratory of Cell Biology, Department of Orthopaedic Surgery, Eberhard Karls University Tuebingen, Tuebingen, Germany.
authors.forename: Sabrina K
authors.initials: SK
authors.lastname: Schweiss
authors.affiliation: Laboratory of Cell Biology, Department of Orthopaedic Surgery, Eberhard Karls University Tuebingen, Tuebingen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hopp
authors.affiliation: Department of Orthopaedic Surgery, Eberhard Karls University, Tuebingen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Traub
authors.affiliation: Department of Orthopaedic Surgery, Eberhard Karls University, Tuebingen, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Kluba
authors.affiliation: Department of Haematology and Oncology, Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.affiliation: Department of Haematology and Oncology, Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany.
authors.forename: Sabine B
authors.initials: SB
authors.lastname: Schleicher
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D001152:Arsenicals; D053823:Hedgehog Proteins; D010087:Oxides; D014157:Transcription Factors; D017964:Itraconazole; D000077237:Arsenic Trioxide