A high-throughput screening identifies histone deacetylase inhibitors as therapeutic agents against medulloblastoma

  • Exp Hematol Oncol. 2019 Nov 15;8:30. doi: 10.1186/s40164-019-0153-x.
Shanshan Zhang   #  1  2  3 ,  Zhaojian Gong   #  2  4 ,  Peter O Oladimeji   #  5 ,  Duane G Currier  5 ,  Qipan Deng  1  2 ,  Ming Liu  2  6 ,  Taosheng Chen  5 ,  Yong Li  1  2
Affiliations
  • 1. 1Section of Epidemiology & Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX USA.
  • 2. 2Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH USA.
  • 3. 3Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China.
  • 4. 4Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China.
  • 5. 5Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN USA.
  • 6. 6State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
  • # Contributed equally.
PMID: 31788346 DOI: 10.1186/s40164-019-0153-x
Abstract

Background: Medulloblastoma is the most frequently occurring malignant brain tumor in children. Current treatment strategies for medulloblastoma include aggressive surgery, cranio-spinal irradiation and Adjuvant chemotherapy. Because current treatments can cause severe long-term side effects and are not curative, successful treatment remains a challenge.

Methods: In this study, we employed a high-throughput cell viability assay to screen 12,800 compounds and to identify drug candidates with anti-proliferative properties for medulloblastoma cells. We also tested these compounds for attenuating medulloblastoma tumor development using mouse xenografts.

Results: We identified two histone deacetylase inhibitors (dacinostat and quisinostat) with anti-proliferative properties for medulloblastoma cells. We showed that both compounds induce cytotoxicity, trigger cell Apoptosis, and block cell cycle progression at the G2/M phase. In addition, dacinostat and quisinostat attenuated xenograft medulloblastoma growth in mice.

Conclusions: Our findings suggest that histone deacetylase inhibitors are potent therapeutic agents against medulloblastoma.

Keywords
Dacinostat; HDAC inhibitors; High-throughput screening; Medulloblastoma; Quisinostat.
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