Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, 34450, Istanbul, Turkey.
Department of Computational Biology, Koç University, 34450, Istanbul, Turkey.
Cell Death Dis. 2019 Nov 26;10(12):894. doi: 10.1038/s41419-019-2107-y.
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.
多形性胶质母细胞瘤（GBM）是最常见和侵袭性最强的原发性脑肿瘤。尽管在手术、化疗和放疗方面最近取得了进展，但 GBM 患者的预后仍然很差，这突显了迫切需要新的治疗策略。TRAIL（TNF 相关凋亡诱导配体）是一种有效的抗癌药物，可选择性诱导癌细胞凋亡。GBM 细胞经常对 TRAIL 产生耐药性，从而使 TRAIL 治疗的临床应用效率降低。在这项研究中，我们采用化学筛选方法，使用一组表观遗传修饰药物库，以确定能够增强 TRAIL 反应的化合物。我们确定真菌代谢产物 chaetocin 是组蛋白甲基转移酶 SUV39H1 的抑制剂，是一种新型 TRAIL 增敏剂。低亚毒性剂量的 chaetocin 和 TRAIL 联合使用可迅速有效地诱导 GBM 细胞凋亡。Chaetocin 还能有效地使 GBM 细胞对 FasL 和 BH3 模拟物等其他促凋亡剂敏感。Chaetocin 介导的凋亡敏化是通过 ROS 生成和随后的 DNA 损伤诱导来实现的，涉及 P53 活性。Chaetocin 诱导的转录组变化显示诱导抗氧化防御机制和 DNA 损伤反应途径。血红素加氧酶 1（HMOX1）是上调基因中的一种，其诱导依赖于 ROS，HMOX1 耗竭增强了 chaetocin 介导的 TRAIL 增敏作用。最后，chaetocin 和 TRAIL 联合治疗在体内显示出疗效。总之，我们的研究结果为 chaetocin 作为一种凋亡启动剂提供了新的作用机制，其与促凋亡治疗的联合可能为 GBM 提供新的治疗方法。
