Chloroquine and hydroxychloroquine in antitumor therapies based on autophagy-related mechanisms

Ferreira, Paulo Michel Pinheiro; Sousa, Rayran Walter Ramos de; Ferreira, José Roberto de Oliveira; Militão, Gardênia Carmen Gadelha; Bezerra, Daniel Pereira

doi:10.1016/j.phrs.2021.105582

Cited by 103 publications

(66 citation statements)

References 76 publications

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“…Since the early months of the pandemic, HCQ, a widely used drug with good safety profile in clinic [19][20][21], has been extensively researched for repurposing in COVID-19 treatment/prevention [3][4][5][6]. HCQ is commonly used in the treatment of a variety of diseases, including malaria, autoimmune disorders, and more recently cancer [19][20][21]. Current knowledge on the mechanisms of action of HCQ is mainly deduced from its inhibitory effects on lysosomal activity and interference with autophagy [19].…”

Section: Discussionmentioning

confidence: 99%

“…Despite the decades-long use of HCQ, originally as an antimalarial drug and later as a therapeutic for autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and other inflammatory rheumatic diseases, the exact mechanisms of action of this drug are only beginning to be elucidated (reviewed in refs. [19][20][21]). HCQ is a derivative of 4-aminoquinoline, which has a characteristic flat aromatic core structure, with a 'basic' side chain (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…More recently, the utility of HCQ, as an anti-neoplastic drug, has also been demonstrated in various types of cancer [25,26]. The anti-cancer properties of HCQ are mostly ascribed to its ability to modulate autophagy [20,27]. As an evolutionarily conserved self-defense mechanism for the degradation of cytoplasmic components, autophagy is essential for the maintenance of intracellular homeostasis and cellular remodeling [23,28], while also playing paradoxical roles in hyper-proliferating, hypoxic, and metabolically stressed cancerous cells [26,29].…”

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%

Section: Introductionmentioning

confidence: 99%

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Hydroxychloroquine induces oxidative DNA damage and mutation in mammalian cells

2021

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“…Autophagy is a continuous process of dynamic development, mainly including the initial stage, extension stage and mature degradation stage of autophagosome, a bilayer membrane structure which fuses into lysosome, and further form autophagolysosomes to degrade the material encapsulated in it and release it for reuse. The autophagic process is regulated by many factors, and more than 40 autophagy related genes (ATG) and corresponding proteins have been found to participate in autophagy regulation (Chou et al, 2021;Ferreira et al, 2021).…”

Section: Autophagic Processmentioning

confidence: 99%

Targeting Autophagy with Natural Compounds in Cancer: A Renewed Perspective from Molecular Mechanisms to Targeted Therapy

et al. 2021

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Natural products are well-characterized to have pharmacological or biological activities that can be of therapeutic benefits for cancer therapy, which also provide an important source of inspiration for discovery of potential novel small-molecule drugs. In the past three decades, accumulating evidence has revealed that natural products can modulate a series of key autophagic signaling pathways and display therapeutic effects in different types of human cancers. In this review, we focus on summarizing some representative natural active compounds, mainly including curcumin, resveratrol, paclitaxel, Bufalin, and Ursolic acid that may ultimately trigger cancer cell death through the regulation of some key autophagic signaling pathways, such as RAS-RAF-MEK-ERK, PI3K-AKT-mTOR, AMPK, ULK1, Beclin-1, Atg5 and p53. Taken together, these inspiring findings would shed light on exploiting more natural compounds as candidate small-molecule drugs, by targeting the crucial pathways of autophagy for the future cancer therapy.

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“…Both converge in the accumulation within endosomes/lysosomes, leading to the interference of the autophagic flux [ 33 – 35 ], disruption of several enzymes (e.g., acid hydrolases and cathepsin B and D lysosomal cysteine proteases) [ 36 , 37 ], inhibition of antigen processing [ 38 , 39 ], and post-translational modification of recently produced proteins [ 35 , 40 ]. In addition, preclinical and clinical investigations are testing the effectiveness of quinines as inhibitors of the autophagy flux to overcome resistance when traditional chemotherapy drugs are used as monotherapy, since the induction of autophagy has been associated with resistance in the therapy of cancer [ 41 , 42 ].…”

Section: Main Textmentioning

confidence: 99%

Aminoquinolines as Translational Models for Drug Repurposing: Anticancer Adjuvant Properties and Toxicokinetic-Related Features

Ferreira

Ferreira²,

Sousa

et al. 2021

Journal of Oncology

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The indiscriminate consumption of antimalarials against coronavirus disease-2019 emphasizes the longstanding clinical weapons of medicines. In this work, we conducted a review on the antitumor mechanisms of aminoquinolines, focusing on the responses and differences of tumor histological tissues and toxicity related to pharmacokinetics. This well-defined analysis shows similar mechanistic forms triggered by aminoquinolines in different histological tumor tissues and under coexposure conditions, although different pharmacological potencies also occur. These molecules are lysosomotropic amines that increase the antiproliferative action of chemotherapeutic agents, mainly by cell cycle arrest, histone acetylation, physiological changes in tyrosine kinase metabolism, inhibition of PI3K/Akt/mTOR pathways, cyclin D1, E2F1, angiogenesis, ribosome biogenesis, triggering of ATM-ATR/p53/p21 signaling, apoptosis, and presentation of tumor peptides. Their chemo/radiotherapy sensitization effects may be an adjuvant option against solid tumors, since 4-aminoquinolines induce lysosomal-mediated programmed cytotoxicity of cancer cells and accumulation of key markers, predominantly, LAMP1, p62/SQSTM1, LC3 members, GAPDH, beclin-1/Atg6, α-synuclein, and granules of lipofuscin. Adverse effects are dose-dependent, though most common with chloroquine, hydroxychloroquine, amodiaquine, and other aminoquinolines are gastrointestinal changes, blurred vision ventricular arrhythmias, cardiac arrest, QTc prolongation, severe hypoglycemia with loss of consciousness, and retinopathy, and they are more common with chloroquine than with hydroxychloroquine and amodiaquine due to pharmacokinetic features. Additionally, psychological/neurological effects were also detected during acute or chronic use, but aminoquinolines do not cross the placenta easily and low quantity is found in breast milk despite their long mean residence times, which depends on the coexistence of hepatic diseases (cancer-related or not), first pass metabolism, and comedications. The low cost and availability on the world market have converted aminoquinolines into “star drugs” for pharmaceutical repurposing, but a continuous pharmacovigilance is necessary because these antimalarials have multiple modes of action/unwanted targets, relatively narrow therapeutic windows, recurrent adverse effects, and related poisoning self-treatment. Therefore, their use must obey strict rules, ethical and medical prescriptions, and clinical and laboratory monitoring.

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Chloroquine and hydroxychloroquine in antitumor therapies based on autophagy-related mechanisms

Cited by 103 publications

References 76 publications

Hydroxychloroquine induces oxidative DNA damage and mutation in mammalian cells

Hydroxychloroquine induces oxidative DNA damage and mutation in mammalian cells

Targeting Autophagy with Natural Compounds in Cancer: A Renewed Perspective from Molecular Mechanisms to Targeted Therapy

Aminoquinolines as Translational Models for Drug Repurposing: Anticancer Adjuvant Properties and Toxicokinetic-Related Features

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