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Norcantharidin impairs medulloblastoma growth by inhibition of Wnt/β-catenin signaling

  • Laboratory Investigation - Human/Animal Tissue
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Abstract

Medulloblastoma is one of the leading causes of morbidity and mortality in pediatric cancer. Wnt-active tumors, an independent molecular subgroup in medulloblastoma, are characterized by a distinct pattern of genomic aberrations. We assessed the anticancer activity of cantharidin and norcantharidin against medulloblastoma, as cell lines in vitro and in athymic nude mice in vivo. Cantharidin and norcantharidin treatment impaired the growth of DAOY and UW228 medulloblastoma cells and promoted the loss of β-catenin activation and the β-catenin nuclearization linked to N-cadherin impairment in vitro. Intra-peritoneal administration of norcantharidin inhibited the growth of intra-cerebellum tumors in orthotopic xenograft nude mice. Analysis of the xenograft tissues revealed enhanced neuronal differentiation and reduced β-catenin expression. Our findings suggest that norcantharidin has potential therapeutic applications in the treatment of medulloblastoma as a result of its ability to cross the blood–brain barrier and its impairment of Wnt-β-catenin signaling.

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Acknowledgments

This study was funded by PRIN (E5AZ5F) 2008 (MZ), AIRC Tumori Pediatrici 2009–2010 (MZ), European GRANT FP6-EET pipeline LSH-CT-2006-037260 (MZ), and FP7-Tumic HEALTH-F2-2008-201662 (MZ). We thank Dr Hans Clevers (University Hospital, Utrecht, The Netherlands) for generously providing the TOPFLASH and FOPFLASH plasmids, and Dr Alexander Martinkosky and Dr Jill Johnson from the Developmental Therapeutics Program (DCTD), National Cancer Institute, Rockville, USA, and Professor Achille Iolascon from DBBM, University of Naples, Italy, for helpful critical observations during the developmental phase of this project.

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Authors and Affiliations

  1. CEINGE, Centro di Ingegneria Genetica, Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80145, Naples, Italy

    Flora Cimmino, Maria Nunzia Scoppettuolo, Marianeve Carotenuto, Pasqualino De Antonellis, Valeria Di Dato, Gennaro De Vita & Massimo Zollo

  2. DBBM, Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131, Naples, Italy

    Flora Cimmino, Maria Nunzia Scoppettuolo, Marianeve Carotenuto, Pasqualino De Antonellis, Valeria Di Dato, Gennaro De Vita & Massimo Zollo

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  1. Flora Cimmino
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  2. Maria Nunzia Scoppettuolo
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  3. Marianeve Carotenuto
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  4. Pasqualino De Antonellis
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  7. Massimo Zollo
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Correspondence to Massimo Zollo.

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Cimmino, F., Scoppettuolo, M.N., Carotenuto, M. et al. Norcantharidin impairs medulloblastoma growth by inhibition of Wnt/β-catenin signaling. J Neurooncol 106, 59–70 (2012). https://doi.org/10.1007/s11060-011-0645-y

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