Targeting hedgehog signalling by arsenic trioxide reduces cell growth and induces apoptosis in rhabdomyosarcoma

Boehme,Karen  A.; Zaborski,Julian  J.; Riester,Rosa; Schweiss,Sabrina  K.; Hopp,Ulrike; Traub,Frank; Kluba,Torsten; Handgretinger,Rupert; Schleicher,Sabine  B.

doi:10.3892/ijo.2015.3293

Targeting hedgehog signalling by arsenic trioxide reduces cell growth and induces apoptosis in rhabdomyosarcoma

Authors:
- Karen A. Boehme
- Julian J. Zaborski
- Rosa Riester
- Sabrina K. Schweiss
- Ulrike Hopp
- Frank Traub
- Torsten Kluba
- Rupert Handgretinger
- Sabine B. Schleicher
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Affiliations: Laboratory of Cell Biology, Department of Orthopaedic Surgery, Eberhard Karls University Tuebingen, Tuebingen, Germany, Department of Orthopaedic Surgery, Eberhard Karls University, Tuebingen, Germany, Department of Haematology and Oncology, Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
Published online on: December 15, 2015 https://doi.org/10.3892/ijo.2015.3293
Pages: 801-812

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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.

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