Alcohol-abuse drug disulfiram targets pediatric glioma via MLL degradation

Autor: S Cantilena, Stefanie Meier, Darren Hargrave, David Michod, John Anderson, Jasper de Boer, Maria Victoria Niklison Chirou, Paolo Salomoni
Rok vydání: 2021
Předmět:
Cancer Research
genetics [Glioma]
metabolism [Myeloid-Lymphoid Leukemia Protein]
metabolism [Histones]
Transcription
Genetic
drug effects [Gene Expression Regulation
Neoplastic]
metabolism [Glioma]
Histones
drug effects [Methylation]
Disulfiram
drug effects [Protein Processing
Post-Translational]
Child
media_common
Drug Synergism
Glioma
metabolism [Lysine]
Gene Expression Regulation
Neoplastic
Alcoholism
therapeutic use [Auranofin]
metabolism [Histone-Lysine N-Methyltransferase]
medicine.symptom
Stem cell
drug effects [Transcription
Genetic]
Myeloid-Lymphoid Leukemia Protein
medicine.drug
Drug
media_common.quotation_subject
Immunology
Down-Regulation
Drug development
Methylation
Article
Cellular and Molecular Neuroscience
Downregulation and upregulation
ddc:570
Auranofin
Cell Line
Tumor
pharmacology [Disulfiram]
drug therapy [Glioma]
medicine
drug therapy [Alcoholism]
Humans
Adverse effect
neoplasms
Cell Proliferation
drug effects [Cell Proliferation]
QH573-671
business.industry
Lysine
drug effects [Proteolysis]
Drug Repositioning
Cancer
Cell Biology
pharmacology [Auranofin]
Histone-Lysine N-Methyltransferase
medicine.disease
CNS cancer
Mechanism of action
drug effects [Down-Regulation]
Proteolysis
Cancer research
Neoplasm Grading
Cytology
business
therapeutic use [Disulfiram]
genetics [Down-Regulation]
Protein Processing
Post-Translational
pathology [Glioma]
Zdroj: Cell Death & Disease
Cell death & disease 12(8), 785 (2021). doi:10.1038/s41419-021-04078-9
Cell Death and Disease, Vol 12, Iss 8, Pp 1-12 (2021)
ISSN: 2041-4889
Popis: 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.
Databáze: OpenAIRE
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