Celastrol-induced degradation of FANCD2 sensitizes pediatric high-grade gliomas to the DNA-crosslinking agent carboplatin

EBioMedicine. 2019 Dec;50:81-92. doi: 10.1016/j.ebiom.2019.10.062. Epub 2019 Nov 14.


Background: Pediatric high-grade gliomas (pHGG) are the leading cause of cancer-related death during childhood. Due to their diffuse growth characteristics, chemoresistance and location behind the blood-brain barrier (BBB), the prognosis of pHGG has barely improved in the past decades. As such, there is a dire need for new therapies that circumvent those difficulties. Since aberrant expression of DNA damage-response associated Fanconi anemia proteins play a central role in the onset and therapy resistance of many cancers, we here investigated if FANCD2 depletion could sensitize pHGG to additional DNA damage.

Methods: We determined the capacity of celastrol, a BBB-penetrable compound that degrades FANCD2, to sensitize glioma cells to the archetypical DNA-crosslinking agent carboplatin in vitro in seven patient-derived pHGG models. In addition, we tested this drug combination in vivo in a patient-derived orthotopic pHGG xenograft model. Underlying mechanisms to drug response were investigated using mRNA expression profiling, western blotting, immunofluorescence, FANCD2 knockdown and DNA fiber assays.

Findings: FANCD2 is overexpressed in HGGs and depletion of FANCD2 by celastrol synergises with carboplatin to induce cytotoxicity. Combination therapy prolongs survival of pHGG-bearing mice over monotherapy and control groups in vivo (P<0.05). In addition, our results suggest that celastrol treatment stalls ongoing replication forks, causing sensitivity to DNA-crosslinking in FANCD2-dependent glioma cells.

Interpretation: Our results show that depletion of FANCD2 acts as a chemo-sensitizing strategy in pHGG. Combination therapy using celastrol and carboplatin might serve as a clinically relevant strategy for the treatment of pHGG.

Funding: This study was funded by a grant from the Children Cancer-Free Foundation (KIKA, project 210). The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Keywords: Celastrol; DNA-crosslinking; FANCD2; Pediatric high-grade glioma; Preclinical therapy development.

MeSH terms

  • Adolescent
  • Animals
  • Carboplatin / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Child
  • Child, Preschool
  • Cross-Linking Reagents / pharmacology*
  • DNA Damage
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics*
  • Fanconi Anemia Complementation Group D2 Protein / genetics*
  • Fanconi Anemia Complementation Group D2 Protein / metabolism*
  • Female
  • Glioma / genetics*
  • Glioma / metabolism*
  • Glioma / pathology
  • Humans
  • Male
  • Mice
  • Neoplasm Grading
  • Pentacyclic Triterpenes
  • Proteolysis / drug effects
  • Triterpenes / pharmacology*
  • Xenograft Model Antitumor Assays


  • Cross-Linking Reagents
  • FANCD2 protein, human
  • Fanconi Anemia Complementation Group D2 Protein
  • Pentacyclic Triterpenes
  • Triterpenes
  • Carboplatin
  • celastrol