ArticleEBioMedicine2019
Celastrol-induced degradation of FANCD2 sensitizes pediatric high-grade gliomas to the DNA-crosslinking agent carboplatin.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 32 citations in OpenAlex.
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- Bacteria-Assisted Celastrol Liposomes for Effective Chemotherapy Against Lung Cancer in Mice Model.International journal of nanomedicine · 2025Article
- Gemcitabine therapeutically disrupts essential SIRT1-mediated p53 repression in atypical teratoid/rhabdoid tumors.Cell reports. Medicine · 2024Article
- Myeloid cells coordinately induce glioma cell-intrinsic and cell-extrinsic pathways for chemoresistance via GP130 signaling.Cell reports. Medicine · 2024Article
- The Role of HIF-1α in Retinopathy of Prematurity: A Review of Current Literature.Journal of clinical medicine · 2024Review
- AURKA and PLK1 inhibition selectively and synergistically block cell cycle progression in diffuse midline glioma.iScience · 2022Article
- Neuroprotective Effects of Celastrol in Neurodegenerative Diseases-Unscramble Its Major Mechanisms of Action and Targets.Aging and disease · 2022Review
- Celastrol Induces Apoptosis and Autophagy via the AKT/mTOR Signaling Pathway in the Pituitary ACTH-secreting Adenoma Cells.Current medical science · 2022Article
- The Mechanisms of Current Platinum Anticancer Drug Resistance in the Glioma.Current pharmaceutical design · 2022Review
- SHP2 inhibition improves celastrol-induced growth suppression of colorectal cancer.Frontiers in pharmacology · 2022Article
- Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas.Cancers · 2021Review
- Defining tumor-associated vascular heterogeneity in pediatric high-grade and diffuse midline gliomas.Acta neuropathologica communications · 2021Article
- Revisiting Platinum-Based Anticancer Drugs to Overcome Gliomas.International journal of molecular sciences · 2021Review
- The forkhead box M1 (FOXM1) expression and antitumor effect of FOXM1 inhibition in malignant rhabdoid tumor.Journal of cancer research and clinical oncology · 2021Article
- Screening of a Focused Ubiquitin-Proteasome Pathway Inhibitor Library Identifies Small Molecules as Novel Modulators of Botulinum Neurotoxin Type A Toxicity.Frontiers in pharmacology · 2021Article
- Identification and Validation of an 11-Ferroptosis Related Gene Signature and Its Correlation With Immune Checkpoint Molecules in Glioma.Frontiers in cell and developmental biology · 2021Article
- Nanotechnology-Based Celastrol Formulations and Their Therapeutic Applications.Frontiers in pharmacology · 2021Review
- Celastrol: A Review of Useful Strategies Overcoming its Limitation in Anticancer Application.Frontiers in pharmacology · 2020Review
Corrections and comments
- Erratum issued
Authors and funding
7 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundPediatric 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.
methodsWe 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.
findingsFANCD2 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.
interpretationOur 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.
fundingThis 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.
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