TY - JOUR
T1 - Alcohol-abuse drug disulfiram targets pediatric glioma via MLL degradation
AU - Meier, Stefanie
AU - Cantilena, Sandra
AU - Niklison Chirou, Maria Victoria
AU - Anderson, John
AU - Hargrave, Darren
AU - Salomoni, Paolo
AU - de Boer, Jasper
AU - Michod, David
N1 - Funding Information:
The authors thank Tony Brooks and Dr. Paola Niola from UCL GOS ICH Genomic Facility for providing assistance with conducting the RNA-seq experiments. We thank Dr. Chris Jones for providing the cell lines and the patient primary cells QCTB R006. This research was funded by grants from the Brain Tumor Charity (BTC 8/197) and The Olivia Hodson Cancer Fund (SR16A26) and supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/8/11
Y1 - 2021/8/11
N2 - Pediatric gliomas comprise a broad range of brain tumors derived from glial cells. While high-grade gliomas are often resistant to therapy and associated with a poor outcome, children with low-grade gliomas face a better prognosis. However, the treatment of low-grade gliomas is often associated with severe long-term adverse effects. This shows that there is a strong need for improved treatment approaches. Here, we highlight the potential for repurposing disulfiram to treat pediatric gliomas. Disulfiram is a drug used to support the treatment of chronic alcoholism and was found to be effective against diverse cancer types in preclinical studies. Our results show that disulfiram efficiently kills pediatric glioma cell lines as well as patient-derived glioma stem cells. We propose a novel mechanism of action to explain disulfiram’s anti-oncogenic activities by providing evidence that disulfiram induces the degradation of the oncoprotein MLL. Our results further reveal that disulfiram treatment and MLL downregulation induce similar responses at the level of histone modifications and gene expression, further strengthening that MLL is a key target of the drug and explaining its anti-oncogenic properties.
AB - Pediatric gliomas comprise a broad range of brain tumors derived from glial cells. While high-grade gliomas are often resistant to therapy and associated with a poor outcome, children with low-grade gliomas face a better prognosis. However, the treatment of low-grade gliomas is often associated with severe long-term adverse effects. This shows that there is a strong need for improved treatment approaches. Here, we highlight the potential for repurposing disulfiram to treat pediatric gliomas. Disulfiram is a drug used to support the treatment of chronic alcoholism and was found to be effective against diverse cancer types in preclinical studies. Our results show that disulfiram efficiently kills pediatric glioma cell lines as well as patient-derived glioma stem cells. We propose a novel mechanism of action to explain disulfiram’s anti-oncogenic activities by providing evidence that disulfiram induces the degradation of the oncoprotein MLL. Our results further reveal that disulfiram treatment and MLL downregulation induce similar responses at the level of histone modifications and gene expression, further strengthening that MLL is a key target of the drug and explaining its anti-oncogenic properties.
UR - http://www.scopus.com/inward/record.url?scp=85112316478&partnerID=8YFLogxK
U2 - 10.1038/s41419-021-04078-9
DO - 10.1038/s41419-021-04078-9
M3 - Article
AN - SCOPUS:85112316478
SN - 2041-4889
VL - 12
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 8
M1 - 785
ER -
