School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea.
Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Republic of Korea.
Biochem Pharmacol. 2020 Aug;178:114098. doi: 10.1016/j.bcp.2020.114098. Epub 2020 Jun 12.
Glioblastoma (GBM) remains one of the most uncompromising cancers, with a median survival of 15 months among those receiving maximal therapy. Therefore, new effective approaches are urgently required for the treatment of GBM. In this study, we show that combined treatments with the flavonoid quercetin and chloroquine (CQ), which is a lysosomotropic agent with antimalarial activity, synergistically induce caspase-independent cell death in malignant glioma cells. The combination of quercetin and CQ triggered excessive expansion of autolysosomes and lysosomes due to overloading with undigested cellular components and protein aggregates, leading to cell death, whereas quercetin alone increased autophagic flux. These results suggest that CQ-mediated lysosomal inhibition prolongs quercetin-mediated autophagic flux, resulting in autophagic catastrophe and severe endoplasmic reticulum (ER) stress. Additionally, we found that 1,4,5-triphosphate receptor (IPR)-mediated Ca release from the ER and the following mitochondrial uniporter (MCU)-mediated Ca influx into mitochondria as well as ROS generation are critically involved in the cytotoxicity by this combination. Collectively, the lysosomal defects induced by quercetin plus CQ may trigger the stress to both the ER and mitochondria and consequently their functional defects, contributing to glioma cell death. The combination of quercetin and CQ may be an effective therapeutic option for GBM.
胶质母细胞瘤（GBM）仍然是最棘手的癌症之一，接受最大治疗的患者的中位生存期为 15 个月。因此，迫切需要新的有效方法来治疗 GBM。在这项研究中，我们表明，类黄酮槲皮素与氯喹（CQ）联合治疗，CQ 是一种具有抗疟活性的溶酶体靶向剂，可协同诱导恶性神经胶质瘤细胞发生 caspase 非依赖性细胞死亡。槲皮素和 CQ 的联合作用导致自噬溶酶体和溶酶体过度扩张，因为未消化的细胞成分和蛋白质聚集体使溶酶体超载，导致细胞死亡，而槲皮素单独增加自噬通量。这些结果表明，CQ 介导的溶酶体抑制延长了槲皮素介导的自噬流，导致自噬崩溃和严重的内质网（ER）应激。此外，我们发现，1,4,5-三磷酸受体（IPR）介导的 ER 中 Ca 释放以及随后的线粒体单向转运蛋白（MCU）介导的 Ca 内流入线粒体以及 ROS 的产生在这种组合的细胞毒性中起着至关重要的作用。总的来说，槲皮素加 CQ 诱导的溶酶体缺陷可能引发 ER 和线粒体的应激及其功能缺陷，导致神经胶质瘤细胞死亡。槲皮素和 CQ 的联合治疗可能是 GBM 的一种有效治疗选择。
