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The Journal of Biological Chemistry 2021Treatments for Alzheimer's disease (AD) directed against the prominent amyloid plaque neuropathology are yet to be proved effective despite many phase 3 clinical trials.... (Review)
Review
Treatments for Alzheimer's disease (AD) directed against the prominent amyloid plaque neuropathology are yet to be proved effective despite many phase 3 clinical trials. There are several other neurochemical abnormalities that occur in the AD brain that warrant renewed emphasis as potential therapeutic targets for this disease. Among those are the elementomic signatures of iron, copper, zinc, and selenium. Here, we review these essential elements of AD for their broad potential to contribute to Alzheimer's pathophysiology, and we also highlight more recent attempts to translate these findings into therapeutics. A reinspection of large bodies of discovery in the AD field, such as this, may inspire new thinking about pathogenesis and therapeutic targets.
Topics: Alzheimer Disease; Animals; Brain; Copper; Ferroptosis; Humans; Iron; Phospholipid Hydroperoxide Glutathione Peroxidase; Plaque, Amyloid; Selenium; Zinc
PubMed: 33219130
DOI: 10.1074/jbc.REV120.008207 -
Pharmacology & Therapeutics Jul 2019Clioquinol, one of the first mass-produced drugs, was considered safe and efficacious for many years. It was used as an antifungal and an antiprotozoal drug until it was... (Review)
Review
Clioquinol, one of the first mass-produced drugs, was considered safe and efficacious for many years. It was used as an antifungal and an antiprotozoal drug until it was linked to an outbreak of subacute myelo-optic neuropathy (SMON), a debilitating disease almost exclusively confined to Japan. Today, new information regarding clioquinol targets and its mechanism of action, as well as genetic variation (SNPs) in efflux transporters in the Japanese population, provide a unique interpretation of the existing phenomena. Further understanding of clioquinol's role in the inhibition of cAMP efflux and promoting apoptosis might offer promise for the treatment of cancer and/or neurodegenerative diseases. Here, we highlight recent developments in the field and discuss possible connections, hypotheses and perspectives in clioquinol-related research.
Topics: ATP-Binding Cassette Transporters; Animals; Anti-Infective Agents; Asian People; Clioquinol; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Humans; Myelitis; Neoplasms; Neurodegenerative Diseases; Optic Neuritis; Polymorphism, Single Nucleotide; Syndrome
PubMed: 30898518
DOI: 10.1016/j.pharmthera.2019.03.009 -
Archives of Microbiology Jul 2022Clioquinol and nitroxoline, two drugs with numerous pharmacological properties fallen into disuse for many decades. The first was considered dangerous due to... (Review)
Review
Clioquinol and nitroxoline, two drugs with numerous pharmacological properties fallen into disuse for many decades. The first was considered dangerous due to contraindications and the second mainly because was taken as ineffective, despite its known antibacterial activity. In the last decades, the advances in pharmaceutical chemistry, molecular biology, toxicology and genetics allowed to better understand the cellular action of these compounds, some toxicological issues and/or activity scopes. Thus, a new opportunity for these drugs to be considered as potential antimicrobial agents has arisen. This review contemplates the trajectory of clioquinol and nitroxoline from their emergence to the present day, emphasizing the new studies that indicate the possibility of reintroduction for specific cases.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Clioquinol; Nitroquinolines
PubMed: 35907036
DOI: 10.1007/s00203-022-03122-2 -
Molecular Brain Dec 2019Alzheimer's disease (AD) is the most devastating neurodegenerative disorder. Due to the increase in population and longevity, incidence will triple by the middle of the... (Review)
Review
Alzheimer's disease (AD) is the most devastating neurodegenerative disorder. Due to the increase in population and longevity, incidence will triple by the middle of the twenty-first century. So far, no treatment has prevented or reversed the disease. More than 20 years of multidisciplinary studies have shown that brain zinc dyshomeostasis may play a critical role in AD progression, which provides encouraging clues for metal-targeted therapies in the treatment of AD. Unfortunately, the pilot clinical application of zinc chelator and/or ionophore strategy, such as the use of quinoline-based compounds, namely clioquinol and PBT2, has not yet been successful. The emerging findings revealed a list of key zinc transporters whose mRNA or protein levels were abnormally altered at different stages of AD brains. Furthermore, specifically modulating the expression of some of the zinc transporters in the central nervous system through genetic methods slowed down or prevented AD progression in animal models, resulting in significantly improved cognitive performance, movement, and prolonged lifespan. Although the underlying molecular mechanisms are not yet fully understood, it shed new light on the treatment or prevention of the disease. This review considers recent advances regarding AD, zinc and zinc transporters, recapitulating their relationships in extending our current understanding of the disease amelioration effects of zinc transport proteins as potential therapeutic targets to cure AD, and it may also provide new insights to identify novel therapeutic strategies for ageing and other neurodegenerative diseases, such as Huntington's and Parkinson's disease.
Topics: Alzheimer Disease; Animals; Brain; Carrier Proteins; Homeostasis; Humans; Molecular Targeted Therapy; Zinc
PubMed: 31818314
DOI: 10.1186/s13041-019-0528-2 -
Metal Ions in Life Sciences Feb 2018Copper homeostasis is tightly regulated in both prokaryotic and eukaryotic cells to ensure sufficient amounts for cuproprotein biosynthesis, while limiting oxidative... (Review)
Review
Copper homeostasis is tightly regulated in both prokaryotic and eukaryotic cells to ensure sufficient amounts for cuproprotein biosynthesis, while limiting oxidative stress production and toxicity. Over the last century, copper complexes have been developed as antimicrobials and for treating diseases involving copper dyshomeostasis (e.g., Wilson's disease). There now exists a repertoire of copper complexes that can regulate bodily copper through a myriad of mechanisms. Furthermore, many copper complexes are now being appraised for a variety of therapeutic indications (e.g., Alzheimer's disease and amyotrophic lateral sclerosis) that require a range of copper-related pharmacological affects. Cancer therapy is also drawing considerable attention since copper has been recognized as a limiting factor for multiple aspects of cancer progression including growth, angiogenesis, and metastasis. Consequently, 'old copper complexes' (e.g., tetrathiomolybdate and clioquinol) have been repurposed for cancer therapy and have demonstrated anticancer activity in vitro and in preclinical models. Likewise, new tailor-made copper complexes have been designed based on structural and biological features ideal for their anticancer activity. Human clinical trials continue to evaluate the therapeutic efficacy of copper complexes as anticancer agents and considerable progress has been made in understanding their pharmacological requirements. In this chapter, we present a historical perspective on the main copper complexes that are currently being repurposed for cancer therapy and detail several of the more recently developed compounds that have emerged as promising anticancer agents. We further provide an overview of the known mechanisms of action, including molecular targets and we discuss associated clinical trials.
Topics: Animals; Antineoplastic Agents; Coordination Complexes; Copper; Drug Design; Drug Repositioning; Humans; Molecular Structure; Neoplasms; Organometallic Compounds; Structure-Activity Relationship
PubMed: 29394035
DOI: 10.1515/9783110470734-022 -
CNS Neuroscience & Therapeutics Jan 2012Clioquinol was produced as a topical antiseptic and marketed as an oral intestinal amebicide in 1934, being used to treat a wide range of intestinal diseases. In the... (Review)
Review
Clioquinol was produced as a topical antiseptic and marketed as an oral intestinal amebicide in 1934, being used to treat a wide range of intestinal diseases. In the early 1970s, it was withdrawn from the market as an oral agent because of its association with subacute myelo-optic neuropathy (SMON), a syndrome that involves sensory and motor disturbances in the lower limbs and visual changes. The first methods for determining plasma and tissue clioquinol (5-chloro-7-iodo-8-quinolinol) levels were set up in the 1970s and involved HPLC separation with UV detection, these were followed by a more sensitive GC method with electron capture detection and a gaschromatographic-massspectrometric (GC-MS) method. Finally, an HPLC method using electrochemical detection has proved to be as highly sensitive and specific as the GC-MS. In rats, mice, rabbits, and hamsters, clioquinol is rapidily absorbed and undergoes first-pass metabolization to glucuronate and sulfate conjugates; the concentrations of the metabolites are higher than those of free clioquinol. Bioavailabilty versus intraperitoneal dosing is about 12%. Dogs and monkeys form fewer conjugates. In man, single-dose concentrations are dose related, and the drug's half-life is 11-14 h. There is no accumulation, and the drug is much less metabolized to conjugates. Clioquinol acts as a zinc and copper chelator. Metal chelation is a potential therapeutic strategy for Alzheimer's disease (AD) because zinc and copper are involved in the deposition and stabilization of amyloid plaques, and chelating agents can dissolve amyloid deposits in vitro and in vivo. In general, the ability of clioquinol to chelate and redistribute metals plays an important role in diseases characterised by Zn, Cu, Fe dyshomeostasis, such as AD and Parkinson's disease, as it reduces oxidation and the amyloid burden. Zinc chelators may also act as anticancer agents. Animal toxicity studies have revealed species-specific differences in neurotoxic responses that are related to the serum levels of clioquinol and metabolites. This is also true in humans, who form fewer conjugates. The results of studies of Alzheimer patients are conflicting and need further confirmation. The potential therapeutic role of the two main effects of MPACs (the regulation of the distribution of metals and antioxidants) has not yet been fully explored.
Topics: Animals; Clinical Trials as Topic; Clioquinol; Disease Models, Animal; Humans; Neurodegenerative Diseases
PubMed: 21199452
DOI: 10.1111/j.1755-5949.2010.00231.x -
Metal Ions in Life Sciences Jan 2019Copper is an essential trace element that plays a critical role in a variety of basic biological functions, and serves as a key component in a number of copper-dependent... (Review)
Review
Copper is an essential trace element that plays a critical role in a variety of basic biological functions, and serves as a key component in a number of copper-dependent enzymes that regulate such processes as cell proliferation, angiogenesis, and motility. A growing body of preclinical work has demonstrated that copper is essential to metastatic cancer progression, and may have a role in tumor growth, epithelial-mesenchymal transition, and the formation of the tumor microenvironment and pre-metastatic niche. As a result, copper depletion has emerged as a novel therapeutic strategy in the treatment of metastatic cancer. We present a review of the physiologic role of copper with a discussion of relevant enzymes of the copper proteome in both normal tissue and in cancer. We conducted a comprehensive review of the available preclinical data of several copper chelation agents, including penicillamine, trientine, disulfiram, clioquinol, and tetrathiomolybdate (TM), across a variety of tumor types. We also present the existing early phase clinical trial data for the use of the copper chelator TM in the treatment of breast cancer and other malignancies.
Topics: Chelating Agents; Clinical Trials as Topic; Copper; Humans; Neoplasms; Proteome; Tumor Microenvironment
PubMed: 30855113
DOI: 10.1515/9783110527872-018 -
Frontiers in Neuroscience 2018As people age, iron deposits in different areas of the brain may impair normal cognitive function and behavior. Abnormal iron metabolism generates hydroxyl radicals... (Review)
Review
As people age, iron deposits in different areas of the brain may impair normal cognitive function and behavior. Abnormal iron metabolism generates hydroxyl radicals through the Fenton reaction, triggers oxidative stress reactions, damages cell lipids, protein and DNA structure and function, and ultimately leads to cell death. There is an imbalance in iron homeostasis in Alzheimer's disease (AD). Excessive iron contributes to the deposition of β-amyloid and the formation of neurofibrillary tangles, which in turn, promotes the development of AD. Therefore, iron-targeted therapeutic strategies have become a new direction. Iron chelators, such as desferoxamine, deferiprone, deferasirox, and clioquinol, have received a great deal of attention and have obtained good results in scientific experiments and some clinical trials. Given the limitations and side effects of the long-term application of traditional iron chelators, alpha-lipoic acid and lactoferrin, as self-synthesized naturally small molecules, have shown very intriguing biological activities in blocking Aβ-aggregation, tauopathy and neuronal damage. Despite a lack of evidence for any clinical benefits, the conjecture that therapeutic chelation, with a special focus on iron ions, is a valuable approach for treating AD remains widespread.
PubMed: 30250423
DOI: 10.3389/fnins.2018.00632 -
BMC Cancer Apr 2018We previously reported that clioquinol acts as a zinc ionophore and inhibits the NF-κB signalling pathway. Other research has demonstrated that zinc deficiency plays a...
BACKGROUND
We previously reported that clioquinol acts as a zinc ionophore and inhibits the NF-κB signalling pathway. Other research has demonstrated that zinc deficiency plays a vital role in the occurrence and development of some solid tumours, and intracellular zinc supplementation may reverse this process and enhance the tumour sensitivity to anticancer treatment. Thus, we investigated the radiosensitization effects of clioquinol combined with zinc on HeLa and MCF-7 cells in vitro.
METHODS
The dose effect of growth inhibition of clioquinol combined with zinc on cell viability was determined by a cell counting kit 8 (CCK-8) assay. The radiosensitization effect of clioquinol combined with zinc and/or MG132 in HeLa and MCF-7 cells was detected by the clonogenic assay. The cell cycle distribution and apoptosis of clioquinol combined with zinc on HeLa cells were analyzed by flow cytometry. A luciferase reporter construct was used to study the effect of clioquinol combined with zinc on NF-κB activity in HeLa cells. DNA double-strand breaks were detected by immunofluorescence. The mRNA and protein levels of ATM were analyzed by quantitative real-time PCR and Western blotting, respectively.
RESULTS
Our research showed that clioquinol combined with zinc markedly increased the radiosensitivity of HeLa and MCF-7 cells in low toxic concentrations and resulted in a post-irradiation decrease in G2 phase arrest and an increase in apoptosis. Clioquinol combined with zinc also inhibited NF-κB activation, decreased ATM expression and increased DNA double-strand breaks (DSBs) induced by ionizing radiation.
CONCLUSIONS
These findings indicated that clioquinol combined with zinc enhanced the radiosensitivity of HeLa and MCF-7 cells by the down-regulation of ATM through the NF-κB signalling pathway.
Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Survival; Clioquinol; DNA Damage; Drug Synergism; Gamma Rays; Gene Expression Regulation, Neoplastic; HeLa Cells; Histones; Humans; NF-kappa B; Radiation-Sensitizing Agents; Signal Transduction; Zinc
PubMed: 29678153
DOI: 10.1186/s12885-018-4264-2 -
International Journal of Surgery... Mar 2015The aim of this study is to investigate the expected adhesion-modifying effect of clinoquinol which has metal-chelating feature that limits the inflammation and...
BACKGROUNDS/AIMS
The aim of this study is to investigate the expected adhesion-modifying effect of clinoquinol which has metal-chelating feature that limits the inflammation and fibroblastic activity.
METHODS
A total of 40 Wistar Albino rats were included, which were divided into 5 groups. Group-1 constituted the sham group. Other groups, adhesions were induced by performing cecal abrasion on the rats. For treatment, saline solution was added to Group-2, carboxymethylcellulose was added to Group-3, methylene blue was added to Group-4, and clioquinol was added to Group-5. Blood samples were obtained from the heart to measure IL-10 and TNF α-levels. Adhesions were evaluated both macroscopically and histopathologically.
RESULTS
Clioquinol reduced adhesions at significant level via decreasing the inflammation and fibroblastic activity in the adhesion-induced rats. At macroscopic level, carboxymethylcellulose and clioquinol were the most potent agents in reducing adhesions. Nonetheless, significant foreign body-reaction was observed in the carboxymethylcellulose-treated group.
CONCLUSIONS
Clioquinol could reduce the formation of intra-abdominal adhesions. It exerts this activity by limiting the inflammation and fibroblastic activity between the intestines and serous surfaces. Furthermore, it does not induce a foreign body reaction. Due to these properties, we conclude that clioquinol can be used as an alternative agent to prevent adhesions.
Topics: Animals; Carboxymethylcellulose Sodium; Cecum; Clioquinol; Inflammation; Interleukin-10; Male; Postoperative Complications; Rats; Rats, Wistar; Tissue Adhesions; Tumor Necrosis Factor-alpha
PubMed: 25638731
DOI: 10.1016/j.ijsu.2015.01.022