Chloroquine Is a Zinc Ionophore

Xue, Jing; Moyer, Amanda; Peng, Bing; Wu, Jinchang; Hannafon, Bethany N.; Ding, Wei

doi:10.1371/journal.pone.0109180

Cited by 218 publications

(222 citation statements)

References 31 publications

(54 reference statements)

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“…Since CQ was reported to have pleiotropic effects on cells [15,38,39,40,41], our results further suggest that, in this NET cell model, cell apoptosis is related to the inhibitory effect of CQ on autophagy, and not to an alternative effect of CQ on the cells. …”

Section: Discussionsupporting

confidence: 67%

“…Considering that autophagy may function as a stress-activated prosurvival mechanism in a NET cell model, we hypothesized that inhibition of autophagy by lysosomal inhibitors could promote cell death and enhance the antitumorigenic effects of PI3K/Akt/mTOR pathway inhibitors. As CQ is known to have pleiotropic effects on cells (not only by inhibiting autophagosome degradation) [15,38,39,40,41], we used both pharmacological and genetic approaches to inhibit autophagy. We show for the first time that treatment with CQ alone or together with mTORi exerts robust inhibitory effects on pancreatic NET cell proliferation and survival.…”

Section: Discussionmentioning

confidence: 99%

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Abrogation of Autophagy by Chloroquine Alone or in Combination with mTOR Inhibitors Induces Apoptosis in Neuroendocrine Tumor Cells

et al. 2015

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Background: Everolimus (RAD001), an mTORC1 inhibitor, demonstrated promising, but limited, anticancer effects in neuroendocrine tumors (NETs). Torin1 (a global mTOR inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) seem to be more effective than RAD001. Autophagy, a degradation pathway that may promote tumor growth, is regulated by mTOR; mTOR inhibition results in stimulation of autophagy. Chloroquine (CQ) inhibits autophagy. Aim: To explore the effect of CQ alone or in combination with RAD001, Torin1 or NVP-BEZ235 on autophagy and on NET cell viability, proliferation and apoptosis. Methods: The NET cell line BON1 was treated with CQ with or without different mTOR inhibitors. siRNA against ATG5/7 was used to genetically inhibit autophagy. Cellular viability was examined by XTT, proliferation by Ki-67 staining and cell cycles by flow cytometry. Apoptosis was analyzed by Western blotting for cleaved caspase 3 and staining for annexin V; autophagy was evaluated by Western blotting and immunostaining for LC3. Results: RAD001, Torin1, NVP-BEZ235 and CQ all decreased BON1 cell viability. The effect of RAD001 was smaller than that of the other mTOR inhibitors or CQ. Torin1 and NVP-BEZ235 markedly inhibited cell proliferation, without inducing apoptosis. CQ similarly decreased cell proliferation, while robustly increasing apoptosis. Treatment with Torin1 or NVP-BEZ235 together with CQ was additive on viability, without increasing CQ-induced apoptosis. Inhibition of autophagy by ATG5/7 knockdown increased apoptosis in the presence or absence of mTOR inhibitors, mimicking the CQ effects. Conclusion: CQ inhibits NET growth by inducing apoptosis and by inhibiting cell proliferation, probably via inhibition of autophagy. CQ may potentiate the antitumor effect of mTOR inhibitors.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Abrogation of Autophagy by Chloroquine Alone or in Combination with mTOR Inhibitors Induces Apoptosis in Neuroendocrine Tumor Cells

et al. 2015

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“…Zinc inhibits SARS-CoVand retrovirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture [43]. There is also evidence that zinc enhances chloroquine intracellular uptake [44]. As such, combining zinc with chloroquine or hydroxychloroquine is intriguing and is currently under investigation.…”

Section: Hydroxychloroquine and Chloroquinementioning

confidence: 99%

An Update on Current Therapeutic Drugs Treating COVID-19

et al. 2020

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The current pandemic of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has presented unprecedented challenges to the healthcare systems in almost every country around the world. Currently, there are no proven effective vaccines or therapeutic agents against the virus. Current clinical management includes infection prevention and control measures and supportive care including supplemental oxygen and mechanical ventilatory support. Evolving research and clinical data regarding the virologic SARS-CoV-2 suggest a potential list of repurposed drugs with appropriate pharmacological effects and therapeutic efficacies in treating COVID-19 patients. In this review, we will update and summarize the most common and plausible drugs for the treatment of COVID-19 patients. These drugs and therapeutic agents include antiviral agents (remdesivir, hydroxychloroquine, chloroquine, lopinavir, umifenovir, favipiravir, and oseltamivir), and supporting agents (Ascorbic acid, Azithromycin, Corticosteroids, Nitric oxide, IL-6 antagonists), among others. We hope that this review will provide useful and most updated therapeutic drugs to prevent, control, and treat COVID-19 patients until the approval of vaccines and specific drugs targeting SARS-CoV-2.

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“…The internalization of zinc ions is largely limited by their incompatibility with the cell membrane chemistry. Chloroquine is a zinc ionophore which increases zinc's uptake by cells thereby promoting its biological effects (71).…”

Section: Discussionmentioning

confidence: 99%

Sphingolipid Biosynthesis Inhibition As A Host Strategy Against Diverse Pathogens

Kumar

Park

Hart

et al. 2020

Preprint

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Chloroquine is an anti-malarial and immunosuppressant drug that has cationic amphipathic chemical properties. We performed genome-wide screens in human cells with chloroquine and several other widely used cationic amphipathic drugs (CADs) including the anti-depressants, sertraline (Zoloft) and fluoxetine (Prozac), the analgesic nortriptyline (Pamelor), the anti-arrhythmic amiodarone (Cordarone), and the anti-hypertensive verapamil (Calan) to characterize their molecular similarities and differences. Despite CADs having different disease indications but consistent with them sharing key chemical properties, we found CADs to have remarkably similar phenotypic profiles compared with non-CADs we and others have previously screened (1–5). The most significant genetic interaction for all CADs was the initiating step in sphingolipid biosynthesis catalyzed by serine palmitoyltransferase (SPT). A comparison of genome-wide screens performed with diverse pathogens from viruses, bacteria, plants, and parasites including Ebola (6), adeno-associated virus AAV2 (7), HIV (8), Rotavirus (9), Influenza A (10), Zika virus (11), Picornavirus (12), Exotoxin A (13), Cholera toxin (14), Type III secretion system and Shiga toxin (15, 16), Ricin toxin (17), and Toxoplasma gondii (18) showed SPT as a top common host factor and 80% overlap overall in top hits specifically with CADs. Potential sphingolipid-mediated mechanisms for the host response- and virulence-modulating effects of CADs involve autophagy and SERPINE1/PAI-1 (plasminogen activator inhibitor-1). Chloroquine has recently shown potential as an anti-viral agent for the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease (19, 20). Our study demonstrates that numerous readily available drugs molecularly function highly similar to chloroquine, which suggests they might be considered for further pre-clinical investigation in the context of SARS-CoV-2. More generally, our work suggests the diverse pathogen mitigating potential of drugs that inhibit host sphingolipid biosynthesis such as CADs.Brief SummaryOur study demonstrates that numerous readily available drugs molecularly function highly similar to chloroquine, which suggests they might be considered for further pre-clinical investigation in the context of SARS-CoV-2.

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Chloroquine Is a Zinc Ionophore

Cited by 218 publications

References 31 publications

Abrogation of Autophagy by Chloroquine Alone or in Combination with mTOR Inhibitors Induces Apoptosis in Neuroendocrine Tumor Cells

Abrogation of Autophagy by Chloroquine Alone or in Combination with mTOR Inhibitors Induces Apoptosis in Neuroendocrine Tumor Cells

An Update on Current Therapeutic Drugs Treating COVID-19

Sphingolipid Biosynthesis Inhibition As A Host Strategy Against Diverse Pathogens

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