The fungal metabolite chaetocin is a sensitizer for pro-apoptotic therapies in glioblastoma

Autor: Nazife Tolay, Ahmet Cingoz, Udo Oppermann, Zeynep Kahya-Yesil, James E. Dunford, Fidan Seker, Fırat Uyulur, Melike Gezen, Batu Erman, Ezgi Ozyerli-Goknar, Alisan Kayabolen, Tugba Bagci-Onder, Ilknur Sur-Erdem, Mehmet Gönen
Přispěvatelé: Uyulur, Fırat, Gönen, Mehmet (ORCID 0000-0002-2483-075X & YÖK ID 237468), Önder, Tuğba Bağcı (ORCID 0000-0003-3646-2613 & YÖK ID 184359), Özyerli-Göknar, Ezgi, Sur-Erdem, İlknur, Şeker, Fidan, Cingoz, Ahmet, Kayabölen, Alişan, Kahya-Yeşil, Zeynep, Gezen, Melike, Tolay, Nazife, Erman, Batu, Dunford, James, Oppermann, Udo, Graduate School of Sciences and Engineering, College of Engineering, School of Medicine, Graduate School of Health Sciences, Department of Computational Sciences and Engineering, Department of Industrial Engineering, Department of Medical Biology and Genetics, Department of Cellular and Molecular Medicine
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
HMOX1
Drug Evaluation
Preclinical
Apoptosis
Piperazines
Fas ligand
Epigenesis
Genetic
TNF-Related Apoptosis-Inducing Ligand
Mice
0302 clinical medicine
Sensitization
lcsh:Cytology
Brain Neoplasms
Drug Synergism
3. Good health
Gene Expression Regulation
Neoplastic
medicine.anatomical_structure
Caspases
030220 oncology & carcinogenesis
Histone methyltransferase
Metabolome
Cell biology
Fas Ligand Protein
Cell Survival
DNA damage
Immunology
bcl-X Protein
Models
Biological
Article
Trail-induced apoptosis
Histone deacetylase inhibitor
Cancer-cells
Up regulation
Death
Activation
Receptor
Ligand
Resistance
Methyltransferase
03 medical and health sciences
Cellular and Molecular Neuroscience
Cell Line
Tumor
medicine
Animals
Humans
RNA
Messenger
lcsh:QH573-671
Cell Proliferation
business.industry
Fungi
Cell Biology
CNS cancer
Heme oxygenase
030104 developmental biology
Cancer cell
Cancer research
Tumor Suppressor Protein p53
Glioblastoma
Reactive Oxygen Species
Transcriptome
business
Heme Oxygenase-1
DNA Damage
Zdroj: Cell Death & Disease
Cell Death and Disease
Cell Death and Disease, Vol 10, Iss 12, Pp 1-20 (2019)
ISSN: 2041-4889
DOI: 10.1038/s41419-019-2107-y
Popis: 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.
Scientific and Technological Research Council of Turkey (TÜBİTAK); European Union (European Union); Horizon 2020; Marie Curie FP7 Career Reintegration Grant; People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme; Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD]; Wellcome; Koç University Center for Translational Medicine (KUTTAM); Cancer Research UK; National Institute for Health Research (NIHR); AbbVie; Bayer Pharma AG; Boehringer Ingelheim; Canada Foundation for Innovation; Eshelman Institute for Innovation; Genome Canada; Johnson & Johnson USA, Janssen Biotech Inc.; Merck KGaA Darmstadt Germany; MSD; Novartis Pharma AG; Ontario Ministry of Economic Development and Innovation; Pfizer; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Takeda Pharmaceutical Company Ltd.
Databáze: OpenAIRE
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