Article ; Online: Chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress.
Toxicology and applied pharmacology
2021 Volume 414, Page(s) 115412
Abstract: COVID-19 is a pandemic with no end in sight. There is only one approved antiviral agent but global stocks are deemed insufficient. Despite in vitro antiviral activity, clinical trials of chloroquine and hydroxychloroquine were disappointing, and they may ...
| Abstract | COVID-19 is a pandemic with no end in sight. There is only one approved antiviral agent but global stocks are deemed insufficient. Despite in vitro antiviral activity, clinical trials of chloroquine and hydroxychloroquine were disappointing, and they may even impair outcomes. Chloroquine causes zebroid deposits reminiscent of Fabry disease (α-galactosidase A deficiency) and endothelial cells are key targets of COVID-19. We have explored the effect of chloroquine on cultured endothelial cells and its modulation by recombinant α-galactosidase A (agalsidase). Following dose-response studies, 0.5 μg/mL chloroquine was added to cultured human endothelial cells. Neutral red and Lysotracker were used to assess lysosomes. Cytotoxicity was evaluated by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) - MTT assay and cell stress by assessing reactive oxygen species (ROS) and nitric oxide (NO). In endothelial cells, chloroquine induced dose-dependent cytotoxicity at in vitro test concentrations for COVID-19 therapy. At a sublethal concentration, chloroquine significantly induced the accumulation of acid organelles (P < 0.05), increased ROS levels, and decreased NO production (P < 0.05). These adverse effects of chloroquine on endothelial cell biology were decreased by agalsidase-β (P < 0.05). Chloroquine-induced endothelial cell cytotoxicity and stress is attenuated by agalsidase-β treatment. This suggests that endothelial cell injury may contribute to the failure of chloroquine as therapy for COVID-19 and may be at least in part related to causing dysfunction of the lysosomal enzyme α-galactosidase A. |
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| MeSH term(s) | COVID-19/drug therapy ; Cell Survival/drug effects ; Cells, Cultured ; Chloroquine/administration & dosage ; Chloroquine/adverse effects ; Chloroquine/therapeutic use ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/metabolism ; Endothelium, Vascular/pathology ; Fabry Disease/chemically induced ; Humans ; Lysosomes/drug effects ; Oxidative Stress/drug effects ; Pandemics ; Reactive Oxygen Species ; SARS-CoV-2 | |||||
| Chemical Substances | Reactive Oxygen Species ; Chloroquine (886U3H6UFF) | |||||
| Language | English | |||||
| Publishing date | 2021-01-21 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 204477-8 | |||||
| ISSN | 1096-0333 ; 0041-008X | |||||
| ISSN (online) | 1096-0333 | |||||
| ISSN | 0041-008X | |||||
| DOI | 10.1016/j.taap.2021.115412 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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