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

摘要: Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain tumor. Despite recent developments in surgery, chemo- radio-therapy, a currently poor prognosis of GBM patients highlights an urgent need for novel treatment strategies. TRAIL (TNF Related Apoptosis Inducing Ligand) potent anti-cancer agent that can induce apoptosis selectively cancer cells. cells frequently develop resistance to which renders clinical application therapeutics inefficient. In this study, we undertook chemical screening approach using library epigenetic modifier drugs identify compounds could augment response. We identified fungal metabolite chaetocin, inhibitor histone methyl transferase SUV39H1, as sensitizer. Combining low subtoxic doses chaetocin resulted very rapid Chaetocin also effectively sensitized further pro-apoptotic agents, such FasL BH3 mimetics. mediated sensitization was achieved through ROS generation consequent DNA damage induction involved P53 activity. induced transcriptomic changes showed antioxidant defense mechanisms response pathways. Heme Oxygenase 1 (HMOX1) among top upregulated genes, whose ROS-dependent HMOX1 depletion enhanced sensitization. Finally, combination revealed efficacy vivo. Taken together, our results provide role priming its with therapies might offer new therapeutic approaches GBMs.