Evaluation of activity and toxicity of combining clioquinol with ciclopirox and terbinafine in alternative models of dermatophytosis.

Dermatophytosis is a superficial fungal infection that affects humans and is very common in small animals. The treatment using the most commonly used antifungals is failing, and new therapeutic alternatives are required to combat the resistance of these fungal infections. Previous studies by the group have shown that clioquinol is an important therapeutic alternative in the treatment of dermatophytosis. The object was to conduct studies of antidermatophytic activity and the irritant potential from the double and triple combinations of clioquinol, terbinafine and ciclopirox in ex vivo and in vivo alternative models. To evaluate the irritant potential of antifungal combinations, the alternative HET-CAM method (chicken egg test chorioallantoic membrane) was used. Ex vivo models were used to assess the effectiveness of antifungal combinations, using pig hooves and veterinary fur. Any possible tissue damage was to assess through in histopathology of swine ears. HET-CAM results showed that all combinations can be classified as non-irritating, corroborated by the results of the histopathological evaluation of the pig's ear skin. Only the double combinations managed to remove 100% of the colony-forming units (CFU) formed on the pig's hooves. The clioquinol + terbinafine combination and the triple combination were more effective than clioquinol + ciclopirox in eradicating the preformed biofilm in fur of veterinary origin. These results show the potential of formulations of clioquinol in combination with antifungals for use in humans and in the veterinary field to combat dermatophytosis, as an important alternative therapy, for use in the near future.

Trace element alterations in Alzheimer's disease: A review.

Dyshomeostasis of trace elements have been implicated in the progression of Alzheimer's disease (AD), which is characterized by amyloid-ß (Aß) plaques. Trace elements are particularly associated with the Aß plaques. Metal-protein attenuating compounds have been developed to inhibit metals from binding to Aß proteins, which result in Aß termination, in the hope of improving cognitive functioning. However, there are still some contradicting reports. This review aims to first establish which trace elements are increased or decreased in the brains of Alzheimer's patients, and secondly, to review the effectiveness of clinical trials with metal-protein attenuating compounds for AD. Studies have consistently reported unchanged or increased iron, contradicting reports for zinc, decreased copper, unchanged or decreased manganese, inconsistent results for calcium, and magnesium seems to be unaffected. However, varied results have been reported for all trace elements. Clinical trials using metal-protein attenuating compounds to treat AD have also reported varied results. Copper chelators have repeatedly been used in clinical trials, even though few studies report increased brain copper levels in AD patients. Homeostasis of copper levels is important since copper has a vital role in several enzymes, such as cytochrome c, Cu/Zn superoxide dismutase and ceruloplasmin. Dyshomeostasis of copper levels can lead to increased oxidative stress and neuronal loss. Future studies should assess a variety of trace element levels in moderately and severely affected AD patients since there are contradicting reports. This review thus provides some insight into trace element alterations in the brains of individuals with AD.

Anti-Aß agents for mild to moderate Alzheimer's disease: systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy and safety of Aß-targeting agents for mild to moderate Alzheimer's disease. METHODS: The MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform search portal were searched from their inception to April 2020. We generated pooled estimates using random effects meta-analyses. RESULTS: Nineteen randomised controlled trials, of which 17 had a low risk of bias, included 12 903 participants. The meta-analysis showed no difference in the cognitive subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog) between anti-Aß drugs and placebo (mean difference (MD): 0.20, 95% CI -0.40 to 0.81; I 2=99.8%; minimal important difference 3.1-3.8 points, moderate-certainty evidence). For ADAS-Cog, results suggested that one drug that increases Aß clearance may differ in effect (MD: -0.96, 95% CI -0.99 to -0.92) from drugs that reduce Aß production (MD: 0.78, 95% CI 0.25 to 1.32) (interaction p<0.000001); this difference also existed in the outcome of MMSE and CDR-SOB. Compared with placebo, anti-Aß drug-related adverse events were as follows: anxiety, depression, diarrhoea, fatigue, rash, syncope and vomit. DISCUSSION: From current evidence, anti-Aß interventions are unlikely to have an important impact on slowing cognitive or functional decline. Although the subgroup analysis suggested possible benefits from Aß clearance drugs, the analysis has limited credibility, and a benefit from drugs that increase clearance, if real, is very small. TRIAL REGISTRATION NUMBER: PROSPERO registration number CRD42019126272.

Copper(II) Binding to PBT2 Differs from That of Other 8-Hydroxyquinoline Chelators: Implications for the Treatment of Neurodegenerative Protein Misfolding Diseases.

PBT2 (5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline) is a small Cu(II)-binding drug that has been investigated in the treatment of neurodegenerative diseases, namely, Alzheimer's disease (AD). PBT2 is thought to be highly effective at crossing the blood-brain barrier and has been proposed to exert anti-Alzheimer's effects through the modulation of metal ion concentrations in the brain, specifically the sequestration of Cu(II) from amyloid plaques. However, despite promising initial results in animal models and in clinical trials where PBT2 was shown to improve cognitive function, larger-scale clinical trials did not find PBT2 to have a significant effect on the amyloid plaque burden compared with controls. We propose that the results of these clinical trials likely point to a more complex mechanism of action for PBT2 other than simple Cu(II) sequestration. To this end, herein we have investigated the solution chemistry of Cu(II) coordination by PBT2 primarily using X-ray absorption spectroscopy (XAS), high-energy-resolution fluorescence-detected XAS, and electron paramagnetic resonance. We propose that a novel bis-PBT2 Cu(II) complex with asymmetric coordination may coexist in solution with a symmetric four-coordinate Cu(II)-bis-PBT2 complex distorted from coplanarity. Additionally, PBT2 is a more flexible ligand than other 8HQs because it can act as both a bidentate and a tridentate ligand as well as coordinate Cu(II) in both 1:1 and 2:1 PBT2/Cu(II) complexes.

Possible role of metal ionophore against zinc induced cognitive dysfunction in D-galactose senescent mice.

Metal ionophores are considered as potential anti-dementia agents, and some are currently undergoing clinical trials. Many metals are known to accumulate and distribute abnormally in the aging brain. Alterations in zinc metal homeostasis in the glutaminergic synapse could contribute to ageing and the pathophysiology of Alzheimer's disease (AD). The present study was designed to investigate the effect of metal ionophores on long term administration of zinc in D-galactose induced senescent mice. The ageing model was established by combined administration of zinc and D-galactose to mice for 6 weeks. A novel metal ionophore, PBT-2 was given daily to zinc-induced d-galactose senescent mice. The cognitive behaviour of mice was monitored using the Morris Water Maze. The anti-oxidant status and amyloidogenic activity in the ageing mouse was measured by determining mito-oxidative parameters and deposition of amyloid ß (Aß) in the brain. Systemic administration of both zinc and D-galactose significantly produced memory deficits, mito-oxidative damage, heightened acetylcholinesterase enzymatic activity and deposition of amyloid-ß. Treatment with PBT-2 significantly improved behavioural deficits, biochemical profiles, cellular damage, and curbed the deposition of APP in zinc-induced senescent mice. These findings suggest that PBT-2, acting as a metal protein attenuating compound, may be helpful in the prevention of AD or alleviation of ageing.

New Hydroxyquinoline-Based Derivatives as Potent Modulators of Amyloid-ß Aggregations.

Copper and zinc have been found to contribute to the burden of amyloid-ß (Aß) aggregations in neurodegenerative Alzheimer's disease (AD). Dysregulation of these metals leads to the generation of reactive oxygen species (ROS) and eventually results in oxidative damage and accumulation of the Aß peptide, which are the key elements of the disease. Aiming to pursue the discovery of new modulators for the disease, we here rationally focused on conjugating the core hydroxyquinoline of the metal-protein attenuating compound PBT2 and the N-methylanilide analogous moiety of the Aß imaging agent to build a new type of multi-target modulators of Aß aggregations. We found that the N,N-dimethylanilinyl imines 7a, 8a, and the corresponding amines 7b, 8b exerted efficient inhibition of Cu(2+) - or Zn(2+) -induced Aß aggregations and significant disassembly of metal-mediated Aß aggregated fibrils. Further, 7a and 7b also exhibited significant ROC scavenging effects compared to PBT2. The results suggested that 7a and 7b are promising lead compounds for the development of a new therapy for AD.

Metal chaperones prevent zinc-mediated cognitive decline.

Zinc transporter-3 (ZnT3) protein is responsible for loading zinc into presynaptic vesicles and consequently controls the availability of zinc at the glutamatergic synapse. ZnT3 has been shown to decline with age and in Alzheimer's disease (AD) and is crucially involved in learning and memory. In this study, we utilised whole animal behavioural analyses in the ZnT3 KO mouse line, together with electrophysiological analysis of long-term potentiation in brain slices from ZnT3 KO mice, to show that metal chaperones (clioquinol, 30 mg/kg/day for 6weeks) can prevent the age-dependent cognitive phenotype that characterises these animals. This likely occurs as a result of a homeostatic restoration of synaptic protein expression, as clioquinol significantly restored levels of various pre- and postsynaptic proteins that are critical for normal cognition, including PSD-95; AMPAR and NMDAR2b. We hypothesised that this clioquinol-mediated restoration of synaptic health resulted from a selective increase in synaptic zinc content within the hippocampus. While we demonstrated a small regional increase in hippocampal zinc content using synchrotron x-ray fluorescence microscopy, further sub-region analyses are required to determine whether this effect is seen in other regions of the hippocampal formation that are more closely linked to the synaptic plasticity effects observed in this study. These data support our recent report on the use of a different metal chaperone (PBT2) to prevent normal age-related cognitive decline and demonstrate that metal chaperones are efficacious in preventing the zinc-mediated cognitive decline that characterises ageing and disease.

Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse.

Iron accumulation and tau protein deposition are pathological features of Alzheimer's (AD) and Parkinson's diseases (PD). Soluble tau protein is lower in affected regions of these diseases, and we previously reported that tau knockout mice display motor and cognitive behavioral abnormities, brain atrophy, neuronal death in substantia nigra, and iron accumulation in the brain that all emerged between 6 and 12 months of age. This argues for a loss of tau function in AD and PD. We also showed that treatment with the moderate iron chelator, clioquinol (CQ) restored iron levels and prevented neuronal atrophy and attendant behavioral decline in 12-month old tau KO mice when commenced prior to the onset of deterioration (6 months). However, therapies for AD and PD will need to treat the disease once it is already manifest. So, in the current study, we tested whether CQ could also rescue the phenotype of mice with a developed phenotype. We found that 5-month treatment of symptomatic (13 months old) tau KO mice with CQ increased nigral tyrosine hydroxylase phosphorylation (which induces activity) and reversed the motor deficits. Treatment also reversed cognitive deficits and raised BDNF levels in the hippocampus, which was accompanied by attenuated brain atrophy, and reduced iron content in the brain. These data raise the possibility that lowering brain iron levels in symptomatic patients could reverse neuronal atrophy and improve brain function, possibly by elevating neurotrophins.

New multi-target-directed small molecules against Alzheimer's disease: a combination of resveratrol and clioquinol.

Alzheimer's disease (AD) is currently one of the most difficult and challenging diseases to treat. Based on the 'multi-target-directed ligands' (MTDLs) strategy, we designed and synthesised a series of new compounds against AD by combining the pharmacophores of resveratrol and clioquinol. The results of biological activity tests showed that the hybrids exhibited excellent MTDL properties: a significant ability to inhibit self-induced ß-amyloid (Aß) aggregation and copper(II)-induced Aß aggregation, potential antioxidant behaviour (ORAC-FL value of 0.9­3.2 Trolox equivalents) and biometal chelation. Among these compounds, (E)-5-(4-hydroxystyryl)quinoline-8-ol (10c) showed the most potent ability to inhibit self-induced Aß aggregation (IC50 = 8.50 µM) and copper(II)-induced Aß aggregation and to disassemble the well-structured Aß fibrils generated by self- and copper(II)-induced Aß aggregation. Note that 10c could also control Cu(I/II)-triggered hydroxyl radical (OH˙) production by halting copper redox cycling via metal complexation, as confirmed by a Cu­ascorbate redox system assay. Importantly, 10c did not show acute toxicity in mice at doses of up to 2000 mg kg−1 and was able to cross the blood­brain barrier (BBB), according to a parallel artificial membrane permeation assay. These results indicate that compound 10c is a promising multifunctional compound for the development of novel drugs for AD.

Metal protein attenuating compounds for the treatment of Alzheimer's dementia.

BACKGROUND: Alzheimer's dementia (AD) may be caused by the formation of extracellular senile plaques comprised of beta-amyloid (Aß). In vitro and mouse model studies have demonstrated that metal protein attenuating compounds (MPACs) promote the solubilisation and clearance of Aß. OBJECTIVES: To evaluate the efficacy of metal protein attenuating compounds (MPACs) for the treatment of cognitive impairment due to Alzheimer's dementia. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 29 July 2010 using the terms: Clioquinol OR PBT1 OR PBT2 OR "metal protein" OR MPACS OR MPAC. SELECTION CRITERIA: Randomised double-blind trials in which treatment with an MPAC was administered to participants with Alzheimer's dementia in a parallel group comparison with placebo were included. DATA COLLECTION AND ANALYSIS: Three review authors (RM, LJ, ELS) independently assessed the quality of trials according to the Cochrane Handbook for Systematic Reviews of Interventions.The primary outcome measure of interest was cognitive function (as measured by psychometric tests). The secondary outcome measures of interest were in the following areas: quality of life, functional performance, effect on carer, biomarkers, safety and adverse effects, and death. MAIN RESULTS: Two MPAC trials were identified. One trial compared clioquinol (PBT1) with placebo in 36 patients and 32 had sufficient data for per protocol analysis. There was no statistically significant difference in cognition (as measured on the Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog)) between the active treatment and placebo groups at 36 weeks. The difference in mean change from baseline ADAS-Cog score in the clioquinol arm compared with the placebo arm at weeks 24 and 36 was a difference of 7.37 (95% confidence interval (CI) 1.51 to 13.24) and 6.36 (95% CI -0.50 to 13.23), respectively.There was no significant impact on non-cognitive symptoms or clinical global impression. One participant in the active treatment group developed neurological symptoms (impaired visual acuity and colour vision) which resolved on cessation of treatment and were possibly attributable to the drug.In the second trial a successor compound, PBT2, was compared with placebo in 78 participants with mild Alzheimer's dementia; all were included in the intention-to-treat analysis. There was no significant difference in the Neuropsychological Test Battery (NTB) composite or memory between placebo and PBT2 in the least squares mean change from baseline at week 12. However, two executive function component tests of the NTB showed significant improvement over placebo in the PBT2 250 mg group from baseline to week 12: category fluency test (2.8 words, 95% CI 0.1 to 5.4; P = 0.041) and trail making part B (-48.0 s, 95% CI -83.0 to -13.0; P = 0.009). In the executive factor Z score, the difference in least squares mean change from baseline at week 12 for PBT2 250 mg compared with placebo was 0·27 (0·01 to 0·53; p=0·042).There was no significant effect on cognition on Mini-Mental State Examination (MMSE) or ADAS-Cog scales. PBT2 had a favourable safety profile. AUTHORS' CONCLUSIONS: There is an absence of evidence as to whether clioquinol (PBT1) has any positive clinical benefit for patients with AD, or whether the drug is safe. We have some concerns about the quality of the study methodology; there was an imbalance in treatment and control groups after randomisation (participants in the active treatment group had a higher mean pre-morbid IQ) and the secondary analyses of results stratified by baseline dementia severity. The planned phase III trial of PBT1 has been abandoned and this compound has been withdrawn from development. The second trial of PBT2 was more rigorously conducted and showed that after 12 weeks this compound appeared to be safe and well tolerated in people with mild Alzheimer's dementia. Larger trials are now required to demonstrate cognitive efficacy.

Is paromomycin the drug of choice for eradication of Blastocystis in adults?

Blastocystis is a protozoan parasite of controversial clinical significance that is often detected in stools of patients with gastrointestinal complaints. Patients infected with Blastocystis and persistent, unexplained gastrointestinal complaints are often treated with the intention to eradicate Blastocystis. However, there is no consensus on the most effective drug. We performed a retrospective follow-up study with a large cohort of patients in which the natural disease course and efficacy of treatment with either paromomycin, clioquinol, or metronidazole were evaluated. With an eradication rate of 77 %, treatment with paromomycin appeared significantly more effective than treatment with clioquinol (38 %), metronidazole (38 %), or no treatment (22 %). This study showed that (1) Blastocystis was frequently observed in the stools of our patient group (34 %), (2) spontaneous clearance of Blastocystis infections occurred only in a small proportion of patients (22 %), and therefore (3) drug treatment is required for more efficient eradication of Blastocystis. Paromomycin exhibited superior performance in comparison to both metronidazole and clioquinol.

Squamous cell carcinoma of the penis and topical combination corticosteroid products: a cautionary case.

Squamous cell carcinoma of the penis is fairly uncommon, but an important clinical entity with significant patient morbidity. Early diagnosis is important to allow for conservative management and to avoid aggressive surgical resection. We present a case of an invasive squamous cell carcinoma of the glans penis, which was treated with topical antifungals and corticosteroids for 2 years prior to diagnosis, necessitating partial glansectomy.

Discovery of Novel 8-Hydroxyquinoline Derivatives with Potent In Vitro and In Vivo Antifungal Activity.

Fungal pathogens can cause life-threatening infections, yet current antifungals are inadequate at treating many of these, highlighting the importance of novel drug discovery. Here, we report hit compound L14, a novel 8-hydroxyquinoline derivative with potent and broad-spectrum antifungal activity. In vitro experiments exhibited that L14 had better activity and lower cytotoxicity than that of clioquinol and showed synergy in combination with fluconazole (FLC). In a Candida albicans-infected murine model, L14 at 2 mg/kg showed better in vivo efficacy than clioquinol at reducing fungal burden and extending the survival of C. albicans-infected mice. In addition, L14 alone or in combination with FLC had significant inhibitory activity against hypha and biofilm formation. Overall, our data indicated that 8-hydroxyquinoline derivative L14 has favorable pharmacokinetics and acceptable safety profiles and could be further investigated as a promising antifungal hit compound.

Understanding Alzheimer's Disease and its Metal Chelation Therapeutics: A Narrative Review.

The neurodegenerative disorders are age-related illnesses that cause the morphology or activity of neurons to deteriorate over time. Alzheimer's disease is the most frequent neurodegenerative illness in the long run. The rate of advancement might vary, even though it is a progressive neurological illness. Various explanations have been proposed, however the true etiology of Alzheimer's disease remains unclear. Most pharmacological interventions are based on the cholinergic theory, that is earliest idea. In accordance with the amyloid hypothesis, the buildup of beta-amyloid in brain regions is the primitive cause of illness. There is no proof that any one strategy is useful in avoiding Alzheimer's disease, though some epidemiological studies have suggested links within various modifiable variables, such as cardiovascular risk, diet and so on. Different metals like zinc, iron, and copper are naturally present in our bodies. In metal chelation therapy drugs are used to jam the metal ions from combining with other molecules in the body. Clioquinol is one of the metal chelation drugs used by researchers. Research on metal chelation is still ongoing. In the present review, we go over the latest developments in prevalence, incidence, etiology, or pathophysiology of our understanding of Alzheimer's disease. Additionally, a brief discussion on the development of therapeutic chelating agents and their viability as Alzheimer's disease medication candidates is presented. We also assess the effect of clioquinol as a potential metal chelator.

Zinc at cytotoxic concentrations affects posttranscriptional events of gene expression in cancer cells.

Zinc at cytotoxic concentrations has been shown to regulate gene transcription in cancer cells, though zinc's involvement in posttranscriptional regulation is less characterized. In this study, we investigated the involvement of cytotoxic zinc in the posttranscriptional steps of gene expression. Clioquinol, a well-established zinc ionophore, was used to raise intracellular zinc to reported cytotoxic levels. The MCF-7 human cancer cell line was applied as a cell model system. Several parameters were used as indictors of posttranscriptional regulation, including p-body formation, microRNA profiling, expression level of proteins known to regulate mRNA degradation, microRNA processing, and protein translation. p-body formation was observed in MCF-7 cells using several molecules known as p-body components. Clioquinol plus zinc enhanced p-body assembly in MCF-7 cells. This enhancement was zinc-specific and could be blocked by a high affinity zinc chelator. The enhancement does not seem to be due to a stress response, as paclitaxel, a commonly used chemotherapeutic, did not cause enhanced p-body formation at a highly cytotoxic concentration. microRNA profiling indicated that clioquinol plus zinc globally down-regulates microRNA expression in this model system, which is associated with the reduced expression of Dicer, an enzyme key to microRNA maturation, and Ago2, a protein essential for microRNA stability. This study demonstrates that ionophoric zinc can induce cytotoxicity in cancer cells by globally regulating posttranscriptional events.

Metal protein attenuating compounds for the treatment of Alzheimer's dementia.

BACKGROUND: Alzheimer's dementia (AD) may be caused by the formation of extracellular senile plaques comprised of beta-amyloid (Aß). In vitro and mouse model studies have demonstrated that metal protein attenuating compounds (MPACs) promote the solubilisation and clearance of Aß. OBJECTIVES: To evaluate the efficacy of metal protein attenuating compounds (MPACs) for the treatment of cognitive impairment due to Alzheimer's dementia. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 29 July 2010 using the terms: Clioquinol OR PBT1 OR PBT2 OR "metal protein" OR MPACS OR MPAC. SELECTION CRITERIA: Randomised double-blind trials in which treatment with an MPAC was administered to participants with Alzheimer's dementia in a parallel group comparison with placebo were included. DATA COLLECTION AND ANALYSIS: Three review authors (RM, LJ, ELS) independently assessed the quality of trials according to the Cochrane Handbook for Systematic Reviews of Interventions.The primary outcome measure of interest was cognitive function (as measured by psychometric tests). The secondary outcome measures of interest were in the following areas: quality of life, functional performance, effect on carer, biomarkers, safety and adverse effects, and death. MAIN RESULTS: Two MPAC trials were identified. One trial compared clioquinol (PBT1) with placebo in 36 patients and 32 had sufficient data for per protocol analysis. There was no statistically significant difference in cognition (as measured on the Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog)) between the active treatment and placebo groups at 36 weeks. The difference in mean change from baseline ADAS-Cog score in the clioquinol arm compared with the placebo arm at weeks 24 and 36 was a difference of 7.37 (95% confidence interval (CI) 1.51 to 13.24) and 6.36 (95% CI -0.50 to 13.23), respectively.There was no significant impact on non-cognitive symptoms or clinical global impression. One participant in the active treatment group developed neurological symptoms (impaired visual acuity and colour vision) which resolved on cessation of treatment and were possibly attributable to the drug.In the second trial a successor compound, PBT2, was compared with placebo in 78 participants with mild Alzheimer's dementia; all were included in the intention-to-treat analysis. There was no significant difference in the Neuropsychological Test Battery (NTB) composite, memory or executive scores between placebo and PBT2 in the least squares mean change from baseline at week 12. However, two executive function component tests of the NTB showed significant improvement over placebo in the PBT2 250 mg group from baseline to week 12: category fluency test (2.8 words, 95% CI 0.1 to 5.4; P = 0.041) and trail making part B (-48.0 s, 95% CI -83.0 to -13.0; P = 0.009). There was no significant effect on cognition on Mini-Mental State Examination (MMSE) or ADAS-Cog scales. PBT2 had a favourable safety profile. AUTHORS' CONCLUSIONS: There is an absence of evidence as to whether clioquinol (PBT1) has any positive clinical benefit for patients with AD, or whether the drug is safe. We have some concerns about the quality of the study methodology; there was an imbalance in treatment and control groups after randomisation (participants in the active treatment group had a higher mean pre-morbid IQ) and the secondary analyses of results stratified by baseline dementia severity. The planned phase III trial of PBT1 has been abandoned and this compound has been withdrawn from development. The second trial of PBT2 was more rigorously conducted and showed that after 12 weeks this compound appeared to be safe and well tolerated in people with mild Alzheimer's dementia. Larger trials are now required to demonstrate cognitive efficacy.

Clioquinol induces cytoplasmic clearance of the X-linked inhibitor of apoptosis protein (XIAP): therapeutic indication for prostate cancer.

Clioquinol (5-chloro-7-iodo-8-quinolinol) is a copper ionophore that was used primarily during the 1950-1970s as an oral antimicrobial agent. It has been established that clioquinol displays toxicity towards malignant cells, inducing caspase-dependent apoptosis. In the present study we therefore investigated the effect of clioquinol on the XIAP [X-linked IAP (inhibitor of apoptosis protein)], as one of its primary functions is to hinder caspase activity and suppress apoptotic cell death. Clioquinol treatment caused cytoplasmic XIAP to rapidly relocate to the nucleus in multiple human transformed (hyperplasic and carcinoma) prostate lines. Clioquinol also caused the cytoplasmic clearance of other IAP family members (cIAP1 and cIAP2). Copper, and no other relevant bivalent metal (e.g. zinc or iron), was exclusively required for clioquinol to elicit an effect on XIAP. We further demonstrated that clioquinol selectively targets and rapidly destroys transformed prostate lines without harming primary prostate epithelial cells. The toxicity of clioquinol was copper-dependent, positively correlated with the level of extracellular copper and could be abrogated by using the copper chelator TTM (tetrathiomolybdate). Clioquinol forced the profound accumulation of intracellular copper with ensuing toxicity influenced by key regulators of cellular copper homoeostasis. Taken together, our results provide significant insight into clioquinol toxicity and reveal an exciting therapeutic approach for the treatment of prostate cancer.

The Zinc Ionophore Clioquinol Reduces Parkinson's Disease Patient-Derived Brain Extracts-Induced Neurodegeneration.

Parkinson's disease (PD) is pathologically characterized by intracellular α-synuclein-rich protein aggregates, named Lewy bodies (LB), and by the progressive loss of dopaminergic neurons in the substantia nigra. Several heavy metals, including zinc (Zn), have been suggested to play a role in PD progression, although the exact role of Zn in neurodegeneration remains to be fully elucidated. To address this gap, we investigated the effects of Zn modulation on the progression of degeneration in mice injected with PD patient-derived LB-extracts carrying toxic α-synuclein aggregates. Zn modulation was achieved using either a clioquinol-enriched diet, a Zn ionophore that redistributes cellular Zn, or a Zn-enriched diet that increases Zn levels. Clioquinol treatment significantly prevented dopaminergic neurodegeneration and reduced α-synuclein-associated pathology in LB-injected mice, while no differences were observed with Zn supplementation. Biochemical analyses further demonstrate that the expression levels of vesicle-specific Zn transporter ZnT3 in the striatum of LB-injected mice treated with clioquinol were decreased, suggesting an intracellular redistribution of Zn. Additionally, we found that clioquinol modulates the autophagy-lysosomal pathway by enhancing lysosomal redistribution within the neuronal compartments. Collectively, we found that in vivo pharmacological chelation of Zn, by dampening Zn-mediated cytotoxicity, can result in an overall attenuation of PD-linked lysosomal alterations and dopaminergic neurodegeneration. The results support zinc chelation as a disease-modifying strategy for treating PD.

Discovery of novel hybrids containing clioquinol-1-benzyl-1,2,3,6-tetrahydropyridine as multi-target-directed ligands (MTDLs) against Alzheimer's disease.

Based on the multitarget strategy, a series of novel clioquinol-1-benzyl-1,2,3,6-tetrahydropyridine hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation in vitro revealed that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE). The optimal compound, 19n, exhibited excellent AChE inhibitory potency (IC50 = 0.11 µM), appropriate metal chelating functions, modulation of AChE- and metal-induced Aß aggregation, neuroprotection against okadaic acid-induced mitochondrial dysfunction and ROS damage, and interesting properties that reduced p-Tau levels in addition to no toxicity on SH-SY5Y cells observed at a concentration up to 50 µM. Most importantly, compound 19n was more well tolerated (>1200 mg/kg) than donepezil (LD50 = 28.124 mg/kg) in vivo. Moreover, compound 19n demonstrated marked improvements in cognitive and spatial memory in two AD mice models (scopolamine-induced and Aß1-42-induced) and suppressed inflammation induced by Aß1-42 in the cortex. The multifunctional profiles of compound 19n demonstrate that it deserves further investigation as a promising lead in the development of innovatively multifunctional drugs for Alzheimer's disease.

Feasibility of Repurposing Clioquinol for Cancer Therapy.

BACKGROUND: Cancer is a prevalent disease in the world and is becoming more widespread as time goes on. Advanced and more effective chemotherapeutics need to be developed for the treatment of cancer to keep up with this prevalence. Repurposing drugs is an alternative to discover new chemotherapeutics. Clioquinol is currently being studied for reposition as an anti-cancer drug. OBJECTIVE: This study aimed to summarize the anti-cancer effects of clioquinol and its derivatives through a detailed literature and patent review and to review their potential re-uses in cancer treatment. METHODS: Research articles were collected through a PubMed database search using the keywords "Clioquinol" and "Cancer." The keywords "Clioquinol Derivatives" and "Clioquinol Analogues" were also used on a PubMed database search to gather research articles on clioquinol derivatives. Patents were gathered through a Google Patents database search using the keywords "Clioquinol" and "Cancer." RESULTS: Clioquinol acts as a copper and zinc ionophore, a proteasome inhibitor, an anti-angiogenesis agent, and is an inhibitor of key signal transduction pathways responsible for its growth-inhibitory activity and cytotoxicity in cancer cells preclinically. A clinical trial conducted by Schimmer et al., resulted in poor outcomes that prompted studies on alternative clioquinol-based applications, such as new combinations, new delivery methods, or new clioquinol-derived analogues. In addition, numerous patents claim alternative uses of clioquinol for cancer therapy. CONCLUSION: Clioquinol exhibits anti-cancer activities in many cancer types, preclinically. Low therapeutic efficacy in a clinical trial has prompted new studies that aim to discover more effective clioquinol- based cancer therapies.