The fungal metabolite chaetocin is a sensitizer for pro-apoptotic therapies in glioblastoma.
Animals
Apoptosis
/ drug effects
Brain Neoplasms
/ drug therapy
Caspases
/ metabolism
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
DNA Damage
Drug Evaluation, Preclinical
Drug Synergism
Epigenesis, Genetic
/ drug effects
Fas Ligand Protein
/ metabolism
Fungi
/ metabolism
Gene Expression Regulation, Neoplastic
/ drug effects
Glioblastoma
/ drug therapy
Heme Oxygenase-1
/ metabolism
Humans
Metabolome
/ drug effects
Mice
Models, Biological
Piperazines
/ pharmacology
RNA, Messenger
/ genetics
Reactive Oxygen Species
/ metabolism
TNF-Related Apoptosis-Inducing Ligand
/ pharmacology
Transcriptome
/ genetics
Tumor Suppressor Protein p53
/ metabolism
bcl-X Protein
/ metabolism
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
26 11 2019
26 11 2019
Historique:
received:
04
03
2019
accepted:
16
10
2019
revised:
12
09
2019
entrez:
28
11
2019
pubmed:
28
11
2019
medline:
1
9
2020
Statut:
epublish
Résumé
Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain tumor. Despite recent developments in surgery, chemo- and radio-therapy, a currently poor prognosis of GBM patients highlights an urgent need for novel treatment strategies. TRAIL (TNF Related Apoptosis Inducing Ligand) is a potent anti-cancer agent that can induce apoptosis selectively in cancer cells. GBM cells frequently develop resistance to TRAIL which renders clinical application of TRAIL therapeutics inefficient. In this study, we undertook a chemical screening approach using a library of epigenetic modifier drugs to identify compounds that could augment TRAIL response. We identified the fungal metabolite chaetocin, an inhibitor of histone methyl transferase SUV39H1, as a novel TRAIL sensitizer. Combining low subtoxic doses of chaetocin and TRAIL resulted in very potent and rapid apoptosis of GBM cells. Chaetocin also effectively sensitized GBM cells to further pro-apoptotic agents, such as FasL and BH3 mimetics. Chaetocin mediated apoptosis sensitization was achieved through ROS generation and consequent DNA damage induction that involved P53 activity. Chaetocin induced transcriptomic changes showed induction of antioxidant defense mechanisms and DNA damage response pathways. Heme Oxygenase 1 (HMOX1) was among the top upregulated genes, whose induction was ROS-dependent and HMOX1 depletion enhanced chaetocin mediated TRAIL sensitization. Finally, chaetocin and TRAIL combination treatment revealed efficacy in vivo. Taken together, our results provide a novel role for chaetocin as an apoptosis priming agent and its combination with pro-apoptotic therapies might offer new therapeutic approaches for GBMs.
Identifiants
pubmed: 31772153
doi: 10.1038/s41419-019-2107-y
pii: 10.1038/s41419-019-2107-y
pmc: PMC6879621
doi:
Substances chimiques
Fas Ligand Protein
0
Piperazines
0
RNA, Messenger
0
Reactive Oxygen Species
0
TNF-Related Apoptosis-Inducing Ligand
0
Tumor Suppressor Protein p53
0
bcl-X Protein
0
chaetocin
28097-03-2
Heme Oxygenase-1
EC 1.14.14.18
Caspases
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
894Subventions
Organisme : Cancer Research UK
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 106169/ZZ14/Z
Pays : United Kingdom
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