Hydroxychloroquine inhibits the mitochondrial antioxidant system in activated T cells

Kim, Man Lyang; Hardy, Melinda Y.; Edgington-Mitchell, Laura E.; Ramarathinam, Sri H.; Chung, Shan Zou; Russell, Amy K.; Currie, Iain; Sleebs, Brad E.; Purcell, Anthony W.; Tye–Din, Jason A.; Wicks, Ian P.

doi:10.1016/j.isci.2021.103509

Cited by 14 publications

(10 citation statements)

References 65 publications

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“…As mentioned above, the autophagosome was first formed to encapsulate the damaged organelles and proteins caused by PTT/PDT at the beginning of the autophagy process and then fused with lysosomes and was further degraded for positive cellular metabolism. HCQ could inhibit the autophagy process through disrupting the fusion between autophagosome and lysosome, thus causing the aggregation of cellular metabolic waste and cell death. − Therefore, detecting the content of autophagosomes plays a key role in evaluating the autophagy behaviors induced by PDT and the autophagy inhibiting effect of HCQ. Herein, we observed the autophagosome content in CAL-27 cells after various treatments using confocal microscopy.…”

Section: Resultsmentioning

confidence: 99%

Cancer Cell Membrane-Coated Nanoparticles for Treatment of Oral Tongue Squamous Cell Carcinoma by Combining Photothermal/Photodynamic Therapy and Autophagy Inhibition

Shi,

Fu,

Hou

et al. 2024

ACS Appl. Nano Mater.

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Photothermal therapy (PTT) and photodynamic therapy (PDT) have been considered as attractive therapeutic treatments for oral tongue squamous cell carcinoma (OTSCC) due to their low toxicity, negligible drug resistance, and minimally invasive properties. Meanwhile, these two treatments can also induce autophagy, which plays an important role in maintaining cellular metabolism and homeostasis through resisting the thermal effect and oxidative stress of PTT and PDT, thus to a certain extent weakening the antitumor efficacy of these two treatments. To improve the antitumor efficiency of PTT/PDT, in this study, we designed a biomimetic nanoparticle treatment system for coloading the photosensitizer and photothermal agent ICG and the autophagy inhibitor hydroxychloroquine (HCQ). Poly(β-amino ester) (PBAE)/polylactic-co-glycolic acid (PLGA) were regarded as the drugs' carrier materials, and cancer cell membrane (CCM) vesicles extracted from OTSCC further encapsulated the PBAE/ PLGA nanocomplex, thus helping to target the delivery of ICG and HCQ to homologous OTSCC cells through efficient selfrecognition and cellular uptake. Upon near-infrared laser irradiation, the nanoparticles exhibited significant antitumor efficacy in vitro and in vivo. Accordingly, this study provided a biomimetic nanoparticle that possessed a notable homologous cancer cell drugdelivery ability and significantly amplified PTT/PDT's effects against OTSCC through autophagy inhibition, which is promising to provide new strategies for the clinical treatment of OTSCC.

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Section: Resultsmentioning

confidence: 99%

Cancer Cell Membrane-Coated Nanoparticles for Treatment of Oral Tongue Squamous Cell Carcinoma by Combining Photothermal/Photodynamic Therapy and Autophagy Inhibition

Shi,

Fu,

Hou

et al. 2024

ACS Appl. Nano Mater.

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“…HCQ-induced autophagy dysfunction has been attributed to apoptotic cell death, particularly in pancreatic cancer cells and effector CD4 T cells 9,40,41 . We recently reported that autophagy dysfunction caused by HCQ is associated with reduced proliferation of activated CD4 T cells 42 . This effect was due to disruption of the mitochondrial antioxidant system and was reversed by the antioxidant N-acetyl cysteine (NAC).…”

Section: Resultsmentioning

confidence: 99%

Hydroxychloroquine impairs mTORC1-dependent cholesterol biosynthesis and sensitizes retinal pigment epithelial cells to UV-induced cell death.

Wicks

Kim²,

Souza³

et al. 2022

Preprint

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Hydroxychloroquine (HCQ) is a widely used and effective immunomodulatory drug. HCQ can cause dose-related retinal damage, thought to be due to inhibitory effects on lysosomes and autophagy. Using a human retinal pigment epithelial cell line (ARPE-19 cells), we confirm HCQ's inhibitory effect on autophagy and report that it inhibits mTORC1-mediated cholesterol biosynthesis. Cellular cholesterol content regulates lysosomal membrane permeability and thereby influences sensitivity to cell death. Cellular cholesterol insufficiency renders ARPE-19 cells more susceptible to a critical environmental threat, namely UV-induced cell death. We also show that HCQ induces apoptosis-independent disruption of phospholipid asymmetry, whereby caspase-independent phosphatidylserine (PS) exposure is mediated by cytosolic cathepsin B. HCQ-induced, caspase-independent PS exposure was inhibitable by the neutral pH-selective cathepsin B inhibitor Z-Arg-Lys-AOMK and was amplified by cholesterol lowering (simvastatin) and depleting (methyl-beta cyclodextrin) agents. We therefore conclude that HCQ also induces the release of lysosomal cathepsin B into the cytosol in response to lysosomal membrane permeability caused by cellular cholesterol insufficiency. We suggest that restricting UV exposure and avoiding cholesterol-lowering agents in combination with long term administration of HCQ might offer preventative strategies to protect against HCQ-induced retinal degeneration. We also provide evidence that neutral pH-selective cathepsin B inhibitors could represent a novel approach to treatment. Our findings may have broader implications for the prevention of retinal cell death and preservation of vision.

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“…The inhibition of autophagy can relieve the development of RA. Kim et al reported that the administration of hydroxychloroquine, a drug used to treat patients with RA, in PBMC-derived human CD4 + T cells inhibits autophagic flux by interfering with mitochondrial superoxide production and induces excessive ROS, thereby inhibiting the proliferation of activated CD4 + T cells ( Kim et al, 2021 ). According to van Loosdregt et al, the administration of hydroxychloroquine in PBMC-derived human CD4 + T cells increases apoptotic CD4 + T cells, suggesting hydroxychloroquine improves joint inflammation by reducing auto-reactive T cells ( Van Loosdregt et al, 2013 ).…”

Section: Chronic Inflammatory Diseasesmentioning

confidence: 99%

The Role of Autophagy in the Function of CD4+ T Cells and the Development of Chronic Inflammatory Diseases

2022

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Uncontrolled acute inflammation progresses to persistent inflammation that leads to various chronic inflammatory diseases, including asthma, Crohn’s disease, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. CD4+ T cells are key immune cells that determine the development of these chronic inflammatory diseases. CD4+ T cells orchestrate adaptive immune responses by producing cytokines and effector molecules. These functional roles of T cells vary depending on the surrounding inflammatory or anatomical environment. Autophagy is an important process that can regulate the function of CD4+ T cells. By lysosomal degradation of cytoplasmic materials, autophagy mediates CD4+ T cell-mediated immune responses, including cytokine production, proliferation, and differentiation. Furthermore, through canonical processes involving autophagy machinery, autophagy also contributes to the development of chronic inflammatory diseases. Therefore, a targeted intervention of autophagy processes could be used to treat chronic inflammatory diseases. This review focuses on the role of autophagy via CD4+ T cells in the pathogenesis and treatment of such diseases. In particular, we explore the underlying mechanisms of autophagy in the regulation of CD4+ T cell metabolism, survival, development, proliferation, differentiation, and aging. Furthermore, we suggest that autophagy-mediated modulation of CD4+ T cells is a promising therapeutic target for treating chronic inflammatory diseases.

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Hydroxychloroquine inhibits the mitochondrial antioxidant system in activated T cells

Cited by 14 publications

References 65 publications

Cancer Cell Membrane-Coated Nanoparticles for Treatment of Oral Tongue Squamous Cell Carcinoma by Combining Photothermal/Photodynamic Therapy and Autophagy Inhibition

Cancer Cell Membrane-Coated Nanoparticles for Treatment of Oral Tongue Squamous Cell Carcinoma by Combining Photothermal/Photodynamic Therapy and Autophagy Inhibition

Hydroxychloroquine impairs mTORC1-dependent cholesterol biosynthesis and sensitizes retinal pigment epithelial cells to UV-induced cell death.

The Role of Autophagy in the Function of CD4+ T Cells and the Development of Chronic Inflammatory Diseases

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