Quercetin and chloroquine synergistically kill glioma cells by inducing organelle stress and disrupting Ca2+ homeostasis.

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 (IP3R)-mediated Ca2+ release from the ER and the following mitochondrial uniporter (MCU)-mediated Ca2+ 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.