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

Abstract

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.

• Authors: Eunjung Jang, In Young Kim, Heeyeon Kim, Dong Min Lee, Dong Young Seo, Ju Ahn Lee, Kyeong Sook Choi, Eunhee Kim
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 178 Pg. 114098 (08 2020) ISSN: 1873-2968 [Electronic] England
• PMID: 32540484 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Calcium Channels
• Drug Combinations
• Inositol 1,4,5-Trisphosphate Receptors
• Reactive Oxygen Species
• mitochondrial calcium uniporter
• Chloroquine
• Quercetin
• Calcium

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Astrocytes (drug effects, metabolism, pathology)
• Autophagosomes (drug effects, metabolism, pathology)
• Autophagy (drug effects)
• Calcium (metabolism)
• Calcium Channels (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chloroquine (pharmacology)
• Drug Combinations
• Drug Synergism
• Endoplasmic Reticulum Stress (drug effects)
• Gene Expression
• Homeostasis (drug effects)
• Humans
• Inositol 1,4,5-Trisphosphate Receptors (genetics, metabolism)
• Lysosomes (drug effects, metabolism, pathology)
• Mitochondria (drug effects, metabolism, pathology)
• Neuroglia (drug effects, metabolism, pathology)
• Quercetin (pharmacology)
• Reactive Oxygen Species (agonists, metabolism)