4.7 Article

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

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CELL DEATH & DISEASE
卷 10, 期 -, 页码 -

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NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-019-2107-y

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资金

  1. Scientific and Technological Research Council of Turkey (TUBITAK) BIDEB Program [2211e]
  2. Marie Curie FP7 Career Reintegration Grant (EC) [618673]
  3. People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA [609305]
  4. Koc University Center for Translational Medicine (KUTTAM)
  5. Cancer Research UK
  6. Oxford NIHR Biomedical Research Centre
  7. AbbVie
  8. Bayer Pharma AG
  9. Boehringer Ingelheim
  10. Canada Foundation for Innovation
  11. Eshelman Institute for Innovation
  12. Genome Canada
  13. Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD] [115766]
  14. Janssen
  15. Merck KGaA Darmstadt Germany
  16. MSD
  17. Novartis Pharma AG
  18. Ontario Ministry of Economic Development and Innovation
  19. Pfizer
  20. Sao Paulo Research Foundation-FAPESP
  21. Takeda
  22. Wellcome [106169/ZZ14/Z]

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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.

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