Chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress

Gregório, PauloC.; Cunha, Regiane Stafim da; BIAGINI, Gleyne Lopes Kujew; Bosquetti, Bruna; Budag, Júlia; Ortíz, Alberto; Sánchez-Niño, María D.; Barreto, Fellype Carvalho; Stinghen, Andréa Emília Marques

doi:10.1016/j.taap.2021.115412

Cited by 22 publications

(15 citation statements)

References 29 publications

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“…These effects are also known to result in impairment of antigen processing and major histocompatibility complex (MHC) class II presentation [44][45][46], which are critical for immunity and inflammatory response [44][45][46]. Notwithstanding the known properties of HCQ to produce ROS [19,[31][32][33][34][35], no data are available on the genotoxic mode of action of this drug in vitro or in vivo [30]. Also, there are limited data on the genotoxic effects of chloroquine, the parent compound of HCQ (see, Fig.…”

Section: Discussionmentioning

confidence: 99%

“…While investigations of the mechanisms of action of HCQ have mainly centered on its intracellular effects, specifically on lysosomal function and activity [19,21,24], very little is known about the interaction of HCQ with DNA, including its DNA damaging-and mutagenic potentials [30]. This is an important gap in knowledge considering that HCQ can produce reactive oxygen species (ROS) [31][32][33][34][35] that are known to cause DNA damage and mutation [36]. The present study is the first investigation of the genotoxicity of HCQ whereby both the DNA damaging-and mutagenic effects of this drug are tested in mammalian cells, at concentrations that are comparable to clinically achievable doses in patient populations.…”

Section: Introductionmentioning

confidence: 99%

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Hydroxychloroquine induces oxidative DNA damage and mutation in mammalian cells

2021

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Since the early stages of the pandemic, hydroxychloroquine (HCQ), a widely used drug with good safety profile in clinic, has come to the forefront of research on drug repurposing for COVID-19 treatment/prevention. Despite the decades-long use of HCQ in the treatment of diseases, such as malaria and autoimmune disorders, the exact mechanisms of action of this drug are only beginning to be understood. To date, no data are available on the genotoxic potential of HCQ in vitro or in vivo. The present study is the first investigation of the DNA damagingand mutagenic effects of HCQ in mammalian cells in vitro, at concentrations that are comparable to clinically achievable doses in patient populations. We demonstrate significant induction of a representative oxidative DNA damage (8-oxodG) in primary mouse embryonic fibroblasts (MEFs) treated with HCQ at 5 and 25 μM concentrations (P = 0.020 and P = 0.029, respectively), as determined by enzyme-linked immunosorbent assay. Furthermore, we show significant mutagenicity of HCQ, manifest as 2.2-and 1.8-fold increases in relative cII mutant frequency in primary and spontaneously immortalized Big Blue® MEFs, respectively, treated with 25 μM dose of this drug (P = 0.005 and P = 0.012, respectively). The observed genotoxic effects of HCQ in vitro, achievable at clinically relevant doses, are novel and important, and may have significant implications for safety monitoring in patient populations. Given the substantial number of the world's population receiving HCQ for the treatment of various chronic diseases or in the context of clinical trials for COVID-19, our findings warrant further investigations into the biological consequences of therapeutic/preventive use of this drug.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hydroxychloroquine induces oxidative DNA damage and mutation in mammalian cells

2021

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“…This line of evidence suggests that endothelial cell injury may contribute to the failure of chloroquine as effective therapy for COVID-19 partially due to lysosomal dysfunction elicited by chloroquine. 36 All these lines of evidence indicate that the endothelium is a bona fide key target for devising and developing anti-COVID-19 therapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

The zinc finger transcription factor, KLF2, protects against COVID-19 associated endothelial dysfunction

Liu

Ding

et al. 2021

Sig Transduct Target Ther

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Coronavirus disease 2019 (COVID-19) is regarded as an endothelial disease (endothelialitis) with its patho-mechanism being incompletely understood. Emerging evidence has demonstrated that endothelial dysfunction precipitates COVID-19 and its accompanying multi-organ injuries. Thus, pharmacotherapies targeting endothelial dysfunction have potential to ameliorate COVID-19 and its cardiovascular complications. The objective of the present study is to evaluate whether kruppel-like factor 2 (KLF2), a master regulator of vascular homeostasis, represents a therapeutic target for COVID-19-induced endothelial dysfunction. Here, we demonstrate that the expression of KLF2 was reduced and monocyte adhesion was increased in endothelial cells treated with COVID-19 patient serum due to elevated levels of pro-adhesive molecules, ICAM1 and VCAM1. IL-1β and TNF-α, two cytokines elevated in cytokine release syndrome in COVID-19 patients, decreased KLF2 gene expression. Pharmacologic (atorvastatin and tannic acid) and genetic (adenoviral overexpression) approaches to augment KLF2 levels attenuated COVID-19-serum-induced increase in endothelial inflammation and monocyte adhesion. Next-generation RNA-sequencing data showed that atorvastatin treatment leads to a cardiovascular protective transcriptome associated with improved endothelial function (vasodilation, anti-inflammation, antioxidant status, anti-thrombosis/-coagulation, anti-fibrosis, and reduced angiogenesis). Finally, knockdown of KLF2 partially reversed the ameliorative effect of atorvastatin on COVID-19-serum-induced endothelial inflammation and monocyte adhesion. Collectively, the present study implicates loss of KLF2 as an important molecular event in the development of COVID-19-induced vascular disease and suggests that efforts to augment KLF2 levels may be therapeutically beneficial.

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“…However, data from clinical trials have not confirmed the benefit of chloroquine and hydroxychloroquine in either prophylaxis or therapy [143] , [144] . Most recently, it has been demonstrated that chloroquine induces endothelial injury through lysosomal dysfunction and oxidative stress [145] , suggesting that endothelial cell injury may account for the failure of chloroquine and hydroxychloroquine as a medication for treating COVID-19.…”

Section: Potential Pharmacotherapy Targeting Vascular Endotheliitismentioning

confidence: 99%

Vascular endotheliitis associated with infections: Its pathogenetic role and therapeutic implication

Hattori

Machida

et al. 2022

Biochemical Pharmacology

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Chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress

Cited by 22 publications

References 29 publications

Hydroxychloroquine induces oxidative DNA damage and mutation in mammalian cells

Hydroxychloroquine induces oxidative DNA damage and mutation in mammalian cells

The zinc finger transcription factor, KLF2, protects against COVID-19 associated endothelial dysfunction

Vascular endotheliitis associated with infections: Its pathogenetic role and therapeutic implication

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