Lysosomotropic agents including azithromycin, chloroquine and hydroxychloroquine activate the integrated stress response

Tian, Ai-Ling; Wu, Qi; Liu, Peng; Zhao, Lu; Martins, Isabelle; Kepp, Oliver; Leduc, Marion

doi:10.1038/s41419-020-03324-w

Cited by 27 publications

(28 citation statements)

References 78 publications

(88 reference statements)

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“…Many chemotherapeutic and lysosomotropic agents cause cell death by inducing apoptosis 4 , 30 . However, MPM-1 did not induce any of the signs that are typically associated with apoptosis, such as exposure of phosphatidylserine, chromatin condensation or depolarized mitochondrial membrane potential.…”

Section: Discussionmentioning

confidence: 99%

The marine natural product mimic MPM-1 is cytolytic and induces DAMP release from human cancer cell lines

Hofsten

Paulsen

Magnussen

et al. 2022

Sci Rep

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Bioprospecting contributes to the discovery of new molecules with anticancer properties. Compounds with cytolytic activity and the ability to induce immunogenic cell death can be administered as intratumoral injections with the aim to activate anti-tumor immune responses by causing the release of tumor antigens as well as damage-associated molecular patterns (DAMPs) from dying cancer cells. In the present study, we report the cytolytic and DAMP-releasing effects of a new natural product mimic termed MPM-1 that was inspired by the marine Eusynstyelamides . We found that MPM-1 rapidly killed cancer cells in vitro by inducing a necrosis-like death, which was accompanied by lysosomal swelling and perturbation of autophagy in HSC-3 (human oral squamous cell carcinoma) cells. MPM-1 also induced release of the DAMPs adenosine triphosphate (ATP) and high mobility group box 1 (HMGB1) from Ramos (B-cell lymphoma) and HSC-3 cells, as well as cell surface expression of calreticulin in HSC-3 cells. This indicates that MPM-1 has the ability to induce immunogenic cell death, further suggesting that it may have potential as a novel anticancer compound.

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Section: Discussionmentioning

confidence: 99%

The marine natural product mimic MPM-1 is cytolytic and induces DAMP release from human cancer cell lines

Hofsten

Paulsen

Magnussen

et al. 2022

Sci Rep

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“…To test if AZM-induced cytotoxicity correlates with lysosomes, we performed live-cell confocal microscopy using pH-sensitive LysoTracker as a specific dye for lysosomes. 7,8 Similar with chloroquine (CQ), AZM caused markedly enlarged, dilatate, and accumulated lysosomes (Figure 3E). Expression of lysosomal associated membrane protein 2 (LAMP2), a specific marker for lysosomes, was significantly enhanced in AZM-treated iPSC-CMs (Figure 3F,G), whereas cathespin D expression was unchanged (Figure S16).…”

Section: F I G U R E 1 Electrophysiological Effects Of Acute Azithromycin (Azm) In Induced Pluripotent Stem Cell-derived Cardiomyocytes (mentioning

confidence: 89%

Characterization of the molecular mechanisms underlying azithromycin‐induced cardiotoxicity using human‐induced pluripotent stem cell‐derived cardiomyocytes

Wang

Pan

Wang

et al. 2021

Clinical & Translational Med

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Dear Editor,We performed a comprehensive study to characterize the molecular mechanisms underlying azithromycin (AZM)induced cardiotoxicity (AIC) using human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Electrophysiologically, high-concentration AZM causes accelerated beating rate and dramatically shortened QT in the absence of proarrhythmic risk. Morphologically, highconcentration AZM interferes with lysosomal activity to impair autophagy flux and autophagosome maturation. The futile and excessive autophagosome formation and accumulation confers vacuole formation, sarcomeric damage, and cardiomyocyte death. Our study uncovered a novel molecular mechanism underlying AIC, and reducing the accumulation of autophagosomes may offer a novel therapeutic strategy for potential AZM-induced cardiovascular risk.AZM is one of the most frequently used antibiotics linked to an increased risk of fatal ventricular arrhythmias and cardiovascular death. 1 Results of AZM-associated cardiovascular risk in existing retrospective studies were discordant, and underlying mechanisms remain unclear. [2][3][4] Three healthy iPSC-CM lines were utilized to investigate AIC, such as arrhythmias, reduced cell viability and morphological damage (Figure S1-S2). Field potentials (FPs) and action potentials were recorded from iPSC-CMs by multi-electrode array and patch clamp, and baseline electrophysiological parameters were comparable between three iPSC-CM lines (Figure S3-S4). Dimethyl sulfoxide (DMSO) and moxifloxacin (MXF) were firstly tested as negative and positive drugs. As expected, DMSO showed negligible effect on FPs, whereas MXF caused prominent prolongation of FP duration (FPD) (Figure 1A-D, Table S1). Having established a stable drug testing platform, we next assessed the acute effects of AZM on electrophysiology (Figure S5). Strikingly, AZM resulted in strong effects on FPs in a concentration-dependent manner (Figure 1E).

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“…In addition to CQ/HCQ, several other lysosomotropic agents have been investigated. One example is azithromycin, a commonly used antibiotic that has similar lysosomotropic property as CQ/HCQ and this pharmacology effect is related to its antibacterial and antiviral function 349,350 . Recent work has indicated that azithromycin is able to block the entry of SARS‐CoV‐2 via disruption of the fusion process between viral and vacuolar membranes, a process related to its lysosomotropic property 351 .…”

Section: Implication Of Autophagy In Health and Diseasesmentioning

confidence: 99%

“…One example is azithromycin, a commonly used antibiotic that has similar lysosomotropic property as CQ/HCQ and this pharmacology effect is related to its antibacterial and antiviral function. 349,350 Recent work has indicated that azithromycin is able to block the entry of SARS-CoV-2 via disruption of the fusion process between viral and vacuolar membranes, a process related to its lysosomotropic property. 351 Moreover, numerous clinical trials have been conducted, using either azithromycin alone or in combination with CQ/HCQ in treatment of COVID-19.…”

Section: 43mentioning

confidence: 99%

Autophagy in health and disease: From molecular mechanisms to therapeutic target

Wang

Shi

et al. 2022

MedComm

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Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double‐membrane structure termed autophagosome and delivered to lysosome for degradation. Over the past two decades, autophagy has been extensively studied, from the molecular mechanisms, biological functions, implications in various human diseases, to development of autophagy‐related therapeutics. This review will focus on the latest development of autophagy research, covering molecular mechanisms in control of autophagosome biogenesis and autophagosome–lysosome fusion, and the upstream regulatory pathways including the AMPK and MTORC1 pathways. We will also provide a systematic discussion on the implication of autophagy in various human diseases, including cancer, neurodegenerative disorders (Alzheimer disease, Parkinson disease, Huntington's disease, and Amyotrophic lateral sclerosis), metabolic diseases (obesity and diabetes), viral infection especially SARS‐Cov‐2 and COVID‐19, cardiovascular diseases (cardiac ischemia/reperfusion and cardiomyopathy), and aging. Finally, we will also summarize the development of pharmacological agents that have therapeutic potential for clinical applications via targeting the autophagy pathway. It is believed that decades of hard work on autophagy research is eventually to bring real and tangible benefits for improvement of human health and control of human diseases.

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Lysosomotropic agents including azithromycin, chloroquine and hydroxychloroquine activate the integrated stress response

Cited by 27 publications

References 78 publications

The marine natural product mimic MPM-1 is cytolytic and induces DAMP release from human cancer cell lines

The marine natural product mimic MPM-1 is cytolytic and induces DAMP release from human cancer cell lines

Characterization of the molecular mechanisms underlying azithromycin‐induced cardiotoxicity using human‐induced pluripotent stem cell‐derived cardiomyocytes

Autophagy in health and disease: From molecular mechanisms to therapeutic target

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