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

Jang, Eue Soon; Kim, In Young; Kim, Heeyeon; Lee, Dong Min; Seo, Dong Young; Lee, Ju Ahn; Choi, Kyeong Sook; Kim, Eun‐Hee

doi:10.1016/j.bcp.2020.114098

Cited by 21 publications

(23 citation statements)

References 46 publications

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“…38,39 It was shown that ROS released during quercetin and chloroquine administration resulted in caspase activation which was particularly involved in the survival of glioma cells. 40 In addition, mitochondria-mediated apoptosis was accompanied by BAX mitochondrial distribution and oligomerization, and caspase 3/caspase 8/caspase 9 activation. 41 This finding is consistent with our current results showing that the cleaved-caspase 3 activated and PI3K/AKT/mTOR signaling pathway were inhibited by the β-mangostin treatment.…”

Section: Discussionmentioning

confidence: 99%

<p>Cytotoxic and Antiproliferative Effects of β-Mangostin on Rat C6 Glioma Cells Depend on Oxidative Stress Induction via PI3K/AKT/mTOR Pathway Inhibition</p>

Chen

et al. 2020

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Background: Glioma is the most common malignant tumor of the nervous system, which accounts for more than 45% of central nervous system tumors and seriously threatens our health. Because of high mortality rate, limitations, and many complications of traditional treatment methods, new treatment methods are urgently needed. β-Mangostin is a natural compound derived from the fruit of Garcinia mangostana L. and it has anticancer activity in several types of cancer cells. However, the antitumor effect of β-mangostin in glioma has not been clarified. Hence, this study aimed to investigate its therapeutic effects on gliomas. Materials and Methods: To study the effect of β-mangostin on glioma cells, cell viability assay, reactive oxygen species production, cell cycle, apoptosis, and mitochondrial membrane potential were evaluated in the C6 cell line in vitro. Immunofluorescence and Western blotting were used to analyze protein expression and phosphorylation to study its mechanism of action. A subcutaneous xenograft model was used to investigate the effect of β-mangostin on tumorigenesis in vivo. Results: We found that β-mangostin can inhibit glioma cell growth and induce oxidative damage in vitro. In addition, it reduces the phosphorylated form levels of PI3K, AKT and mTOR. Furthermore, the phosphorylated form levels of PI3K, AKT and mTOR were increased after the PI3K inhibitor was added. In vivo experiments showed that βmangostin can inhibit tumor growth as shown by its reduced size and weight. Conclusion: This study suggests that β-mangostin can inhibit cell proliferation and induce oxidative damage in cells. It is the first study to demonstrate that β-mangostin induces oxidative damage in glioma cells by inhibiting the PI3K/AKT/mTOR signaling pathway.

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Section: Discussionmentioning

confidence: 99%

<p>Cytotoxic and Antiproliferative Effects of β-Mangostin on Rat C6 Glioma Cells Depend on Oxidative Stress Induction via PI3K/AKT/mTOR Pathway Inhibition</p>

Chen

et al. 2020

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“…ER stress, associated with the upregulation of ATF4 and CHOP and the buildup of ubiquitinated proteins, leads to calcium (Ca 2+ ) release into the cytosol. Intracellular Ca 2+ then enters mitochondria via the mitochondrial Ca 2+ uniporter (MCU); increased mitochondrial calcium concentrations ([Ca 2+ ] m ) upregulate the generation of reactive oxygen species (ROS), which in turn contribute to caspase-induced apoptosis [ 43 ].…”

Section: Mechanisms Of Gbm and Synergistic Flavonoid-chemotherapeutic Effectsmentioning

confidence: 99%

“…Similarly, Wang et al demonstrated synergy between hispidulin and TMZ, with CI = 0.584 [ 37 ]. Synergistic effects of EGCG–TMZ, quercetin–chloroquine, quercetin–NaB, chrysin–ATO, and silibinin–ATO combinations were likewise justified with CI < 1 [ 32 , 43 , 45 , 46 ].…”

Section: Key Considerations and Challengesmentioning

confidence: 99%

Flavonoids Synergistically Enhance the Anti-Glioblastoma Effects of Chemotherapeutic Drugs

et al. 2021

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Flavonoids are polyphenolic plant secondary metabolites with pleiotropic biological properties, including anti-cancer activities. These natural compounds have potential utility in glioblastoma (GBM), a malignant central nervous system tumor derived from astrocytes. Conventional GBM treatment modalities such as chemotherapy, radiation therapy, and surgical tumor resection are beneficial but limited by extensive tumor invasion and drug/radiation resistance. Therefore, dietary flavonoids—with demonstrated anti-GBM properties in preclinical research—are potential alternative therapies. This review explores the synergistic enhancement of the anti-GBM effects of conventional chemotherapeutic drugs by flavonoids. Primary studies published between 2011 and 2021 on flavonoid–chemotherapeutic synergy in GBM were obtained from PubMed. These studies demonstrate that flavonoids such as chrysin, epigallocatechin-3-gallate (EGCG), formononetin, hispidulin, icariin, quercetin, rutin, and silibinin synergistically enhance the effects of canonical chemotherapeutics. These beneficial effects are mediated by the modulation of intracellular signaling mechanisms related to apoptosis, proliferation, autophagy, motility, and chemoresistance. In this light, flavonoids hold promise in improving current therapeutic strategies and ultimately overcoming GBM drug resistance. However, despite positive preclinical results, further investigations are necessary before the commencement of clinical trials. Key considerations include the bioavailability, blood–brain barrier (BBB) permeability, and safety of flavonoids; optimal dosages of flavonoids and chemotherapeutics; drug delivery platforms; and the potential for adverse interactions.

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“…Quercetin (30 µmol/L) in combination with Tmz (100-200 µmol/L) promoted Tmz-induced growth inhibition in U87 and U251 via Hsp27 inhibition [293]. Quercetin combination with chloroquine (CQ) induced caspasedependent apoptosis, autophagic inhibition, and lysosomal suppression in T98G cells [294]. Additionally, quercetin (50 µM) and CQ (20 µM) induced ER stress in T98G cells.…”

Section: Phytochemicals and Nanoparticles In Hgg 61 Flavonoidsmentioning

confidence: 99%

Challenges and Perspectives of Standard Therapy and Drug Development in High-Grade Gliomas

et al. 2021

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Despite their low incidence rate globally, high-grade gliomas (HGG) remain a fatal primary brain tumor. The recommended therapy often is incapable of resecting the tumor entirely and exclusively targeting the tumor leads to tumor recurrence and dismal prognosis. Additionally, many HGG patients are not well suited for standard therapy and instead, subjected to a palliative approach. HGG tumors are highly infiltrative and the complex tumor microenvironment as well as high tumor heterogeneity often poses the main challenges towards the standard treatment. Therefore, a one-fit-approach may not be suitable for HGG management. Thus, a multimodal approach of standard therapy with immunotherapy, nanomedicine, repurposing of older drugs, use of phytochemicals, and precision medicine may be more advantageous than a single treatment model. This multimodal approach considers the environmental and genetic factors which could affect the patient’s response to therapy, thus improving their outcome. This review discusses the current views and advances in potential HGG therapeutic approaches and, aims to bridge the existing knowledge gap that will assist in overcoming challenges in HGG.

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

Cited by 21 publications

References 46 publications

<p>Cytotoxic and Antiproliferative Effects of β-Mangostin on Rat C6 Glioma Cells Depend on Oxidative Stress Induction via PI3K/AKT/mTOR Pathway Inhibition</p>

<p>Cytotoxic and Antiproliferative Effects of β-Mangostin on Rat C6 Glioma Cells Depend on Oxidative Stress Induction via PI3K/AKT/mTOR Pathway Inhibition</p>

Flavonoids Synergistically Enhance the Anti-Glioblastoma Effects of Chemotherapeutic Drugs

Challenges and Perspectives of Standard Therapy and Drug Development in High-Grade Gliomas

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