New insights into mechanisms of therapeutic effects of antimalarial agents in SLE

Wallace, Daniel J.; Gudsoorkar, Vineet; Weisman, Michael H.; Venuturupalli, Swamy R.

doi:10.1038/nrrheum.2012.106

Cited by 189 publications

(145 citation statements)

References 98 publications

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“…They are known to have multiple modes of action, but precisely which mechanism(s) are responsible for their beneficial action is uncertain (22). It was shown that AMDs can attenuate IFN-a production by plasmacytoid dendritic cells due to a reduced activation of TLR associated with AMDs' known ability to alter endosomal maturation (23).…”

Section: Amds Inhibit Ifn-b Expressionmentioning

confidence: 99%

Cutting Edge: Antimalarial Drugs Inhibit IFN-β Production through Blockade of Cyclic GMP-AMP Synthase–DNA Interaction

Woodward

Sasaki

et al. 2015

The Journal of Immunology

175

177

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Type I IFN is strongly implicated in the pathogenesis of systemic autoimmune diseases, such as lupus, and rare monogenic IFNopathies, including Aicardi–Goutières syndrome. Recently, a new DNA-activated pathway involving the enzyme cyclic GMP-AMP synthase (cGAS) was described and potentially linked to Aicardi–Goutières syndrome. To identify drugs that could potentially inhibit cGAS activity, we performed in silico screening of drug libraries. By computational analysis, we identified several antimalarial drugs (AMDs) that were predicted to interact with the cGAS/dsDNA complex. Our studies validated that several AMDs were effective inhibitors of IFN-β production and that they functioned by inhibiting dsDNA stimulation of cGAS. Because AMDs have been widely used in human diseases and have an excellent safety profile, our findings suggest new therapeutic strategies for the treatment of severe debilitating diseases associated with type I IFNs due to cGAS activation.

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Section: Amds Inhibit Ifn-b Expressionmentioning

confidence: 99%

Cutting Edge: Antimalarial Drugs Inhibit IFN-β Production through Blockade of Cyclic GMP-AMP Synthase–DNA Interaction

Woodward

Sasaki

et al. 2015

The Journal of Immunology

175

177

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“…The pharmacologic effects of QNC remain incompletely defined but include the inhibition of nucleic acid synthesis through DNA intercalation and antiprostaglandin and antiplatelet effects due to the inhibition of phospholipase A2 and antilipolytic activity, the inhibition of platelet aggregation, and accumulation within neutrophils (9)(10)(11)(12).…”

mentioning

confidence: 99%

Quinacrine Inhibits Candida albicans Growth and Filamentation at Neutral pH

Kulkarny

Chavez-Dozal

Rane

et al. 2014

Antimicrob Agents Chemother

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Candida albicans is a common cause of catheter-related bloodstream infections (CR-BSI), in part due to its strong propensity to form biofilms. Drug repurposing is an approach that might identify agents that are able to overcome antifungal drug resistance within biofilms. Quinacrine (QNC) is clinically active against the eukaryotic protozoan parasites Plasmodium and Giardia. We sought to investigate the antifungal activity of QNC against C. albicans biofilms. C. albicans biofilms were incubated with QNC at serially increasing concentrations (4 to 2,048 g/ml) and assessed using a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay in a static microplate model. Combinations of QNC and standard antifungals were assayed using biofilm checkerboard analyses. To define a mechanism of action, QNC was assessed for the inhibition of filamentation, effects on endocytosis, and pH-dependent activity. High-dose QNC was effective for the prevention and treatment of C. albicans biofilms in vitro. QNC with fluconazole had no interaction, while the combination of QNC and either caspofungin or amphotericin B demonstrated synergy. QNC was most active against planktonic growth at alkaline pH. QNC dramatically inhibited filamentation. QNC accumulated within vacuoles as expected and caused defects in endocytosis. A tetracycline-regulated VMA3 mutant lacking vacuolar ATPase (V-ATPase) function demonstrated increased susceptibility to QNC. These experiments indicate that QNC is active against C. albicans growth in a pH-dependent manner. Although QNC activity is not biofilm specific, QNC is effective in the prevention and treatment of biofilms. QNC antibiofilm activity likely occurs via several independent mechanisms: vacuolar alkalinization, inhibition of endocytosis, and impaired filamentation. Further investigation of QNC for the treatment and prevention of biofilm-related Candida CR-BSI is warranted.

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“…Another Toll like receptors (TLR)-independent mechanism by HCQ may indicate its cholesterol lowering effect through upregulation of the LDL receptor gene transcription, LDL receptors capacity stimulation and enhancement of LDL removal from plasma by LDL receptors [26]. Several authors have also approved that the hypolipidemic effect of HCQ is due to its systemic inflammation control [27].…”

Section: Discussionmentioning

confidence: 99%

The Effect of Hydroxychloroquine Treatment on Blood Sugar Level, Serum Lipid Profile and the Retina in Systemic Lupus Erythematosus Patients

Sarhan¹,

Shaban²,

Hamid³

et al. 2016

Med-Science

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New insights into mechanisms of therapeutic effects of antimalarial agents in SLE

Cited by 189 publications

References 98 publications

Cutting Edge: Antimalarial Drugs Inhibit IFN-β Production through Blockade of Cyclic GMP-AMP Synthase–DNA Interaction

Cutting Edge: Antimalarial Drugs Inhibit IFN-β Production through Blockade of Cyclic GMP-AMP Synthase–DNA Interaction

Quinacrine Inhibits Candida albicans Growth and Filamentation at Neutral pH

The Effect of Hydroxychloroquine Treatment on Blood Sugar Level, Serum Lipid Profile and the Retina in Systemic Lupus Erythematosus Patients

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