Panobinostat, a histone deacetylase inhibitor, suppresses leptomeningeal seeding in a medulloblastoma animal model

  • Phi J
  • Choi S
  • Kwak P
  • et al.
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Abstract

// Ji Hoon Phi 1, 2, 3, * , Seung Ah Choi 1, 2, * , Pil Ae Kwak 1, 2 , Ji Yeoun Lee 1, 3, 4 , Kyu-Chang Wang 1, 3 , Do Won Hwang 5 and Seung-Ki Kim 1, 2, 3 1 Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul, Korea 2 Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Korea 3 Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea 4 Department of Anatomy, Seoul National University Hospital, Seoul, Korea 5 Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Seung-Ki Kim, email: nsthomas@snu.ac.kr Do Won Hwang, email: hdw6592@hanmail.net Keywords: medulloblastoma, leptomeningeal seeding, histone deacetylase inhibitor, anti-cancer therapy, bioluminescence imaging Received: February 28, 2017      Accepted: April 25, 2017      Published: May 24, 2017 ABSTRACT Leptomeningeal seeding is a strong negative prognostic factor for medulloblastoma (MB). The mechanism of leptomeningeal seeding is unclear but may involve epigenetic regulation. In this study, we evaluated the feasibility of a histone deacetylase (HDAC) inhibitor, panobinostat, in the suppression of MB leptomeningeal seeding. Panobinostat decreased the cell viability and proliferation, inducing cell cycle arrest and apoptosis in MB cell lines. The migration and adhesion capabilities were significantly decreased. Panobinostat effectively down-regulated protein expression of CCND1 and ID3 which has been associated with leptomeningeal seeding of MB. After panobinostat treatment, neurophil-like cellular processes developed and expression of synaptophysin and NeuroD1 was increased, indicating neuronal differentiation. In MB leptomeningeal seeding in vivo model, the panobinostat-treated group showed significantly decreased spinal leptomeningeal seeding and a survival benefit. The findings demonstrate that panobinostat suppresses MB leptomeningeal seeding through the down-regulation of ID3 and the induction of neuronal differentiation. An HDAC inhibitor might be a potent treatment option for the treatment of MB patients with leptomeningeal seeding.

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Phi, J. H., Choi, S. A., Kwak, P. A., Lee, J. Y., Wang, K.-C., Hwang, D. W., & Kim, S.-K. (2017). Panobinostat, a histone deacetylase inhibitor, suppresses leptomeningeal seeding in a medulloblastoma animal model. Oncotarget, 8(34). https://doi.org/10.18632/oncotarget.18132

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