title: Arsenic trioxide induces Noxa-dependent apoptosis in rhabdomyosarcoma cells and synergizes with antimicrotubule drugs.
abstract: The prognosis of metastatic or relapsed rhabdomyosarcoma (RMS) is poor, highlighting the need of new treatment options. In the present study, we evaluated the in vitro efficacy of arsenic trioxide (ATO) in RMS, a FDA-approved drug used in pediatric leukemia. Here, we report that ATO exerts antitumor activity against RMS cells both as single agent and in combination with microtubule-targeting drugs. Monotherapy with ATO reduces cell viability, triggers apoptosis and suppresses clonogenic survival of RMS cells, at least in part, by transcriptional induction of the proapoptotic BH3-only protein Noxa. siRNA-mediated knockdown of Noxa significantly rescues ATO-mediated cell death, demonstrating that Noxa is required for cell death. Also, ATO suppresses endogenous Hedgehog (Hh) signaling, as it significantly reduces Gli1 transcriptional activity and expression levels of several Hh target genes. Furthermore, we identify synergistic induction of apoptosis by ATO together with several antimicrotubule agents including vincristine (VCR), vinblastine and eribulin. The addition of the broad-range caspase inhibitor zVAD.fmk or overexpression of the antiapoptotic protein Bcl-2 significantly reduce ATO/VCR-induced cell death, indicating that the ATO/VCR combination triggers caspase-dependent apoptosis via the mitochondrial pathway. In summary, ATO exerts antitumor activity against RMS, especially in combination with antimicrotubule drugs. These findings have important implications for the development of novel therapeutic strategies for RMS.
authors: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, Johann Wolfgang Goethe-University, Frankfurt, Germany.
authors: Michael Torsten
authors: MT
authors: Meister
authors: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Cathinka
authors: C
authors: Boedicker
authors: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany.
authors: Ulrike
authors: U
authors: Graab
authors: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany.
authors: Manuela
authors: M
authors: Hugle
authors: Department of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.
authors: Heidi
authors: H
authors: Hahn
authors: German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, Johann Wolfgang Goethe-University, Frankfurt, Germany.
authors: Thomas
authors: T
authors: Klingebiel
authors: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: simone.fulda@kgu.de.
authors: Simone
authors: S
authors: Fulda
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005663:Furans / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D007659:Ketones / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010087:Oxides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D050257:Tubulin Modulators / Q000494:pharmacology*; D015854:Up-Regulation; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics / Q000378:metabolism; D000095662:Polyether Polyketides
chemical_list: D000077237:Arsenic Trioxide; D001152:Arsenicals; D061945:Caspase Inhibitors; D005663:Furans; D053823:Hedgehog Proteins; D007659:Ketones; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D050257:Tubulin Modulators; D014747:Vinblastine; D014750:Vincristine; D000071676:Zinc Finger Protein GLI1; C400551:GLI1 protein, human; C498702:PMAIP1 protein, human; C490954:eribulin; D000095662:Polyether Polyketides
keywords: Apoptosis; Arsenic trioxide; Cell death; Hedgehog; Noxa; Rhabdomyosarcoma