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Journal of Experimental & Clinical... Sep 2022Elesclomol is an anticancer drug that targets mitochondrial metabolism. In the past, elesclomol was recognized as an inducer of oxidative stress, but now it has also... (Review)
Review
Elesclomol is an anticancer drug that targets mitochondrial metabolism. In the past, elesclomol was recognized as an inducer of oxidative stress, but now it has also been found to suppress cancer by inducing cuproptosis. Elesclomol's anticancer activity is determined by the dependence of cancer on mitochondrial metabolism. The mitochondrial metabolism of cancer stem cells, cancer cells resistant to platinum drugs, proteasome inhibitors, molecularly targeted drugs, and cancer cells with inhibited glycolysis was significantly enhanced. Elesclomol exhibited tremendous toxicity to all three kinds of cells. Elesclomol's toxicity to cells is highly dependent on its transport of extracellular copper ions, a process involved in cuproptosis. The discovery of cuproptosis has perfected the specific cancer suppressor mechanism of elesclomol. For some time, elesclomol failed to yield favorable results in oncology clinical trials, but its safety in clinical application was confirmed. Research progress on the relationship between elesclomol, mitochondrial metabolism and cuproptosis provides a possibility to explore the reapplication of elesclomol in the clinic. New clinical trials should selectively target cancer types with high mitochondrial metabolism and attempt to combine elesclomol with platinum, proteasome inhibitors, molecularly targeted drugs, or glycolysis inhibitors. Herein, the particular anticancer mechanism of elesclomol and its relationship with mitochondrial metabolism and cuproptosis will be presented, which may shed light on the better application of elesclomol in clinical tumor treatment.
Topics: Copper; Humans; Hydrazines; Ionophores; Neoplasms; Platinum; Proteasome Inhibitors
PubMed: 36089608
DOI: 10.1186/s13046-022-02485-0 -
Current Opinion in Chemical Biology Apr 2017Metal dyshomeostasis is involved in the pathogenesis and progression of diseases including cancer and neurodegenerative diseases. Metal chelators and ionophores are well... (Review)
Review
Metal dyshomeostasis is involved in the pathogenesis and progression of diseases including cancer and neurodegenerative diseases. Metal chelators and ionophores are well known modulators of transition metal homeostasis, and a number of these molecules are in clinical trials. Metal-binding compounds are not the only drugs capable of targeting transition metal homeostasis. This review presents recent highlights in the development of chelators and ionophores for the treatment of cancer and neurodegenerative disease. Moreover, we discuss the development of small molecules that alter copper and iron homeostasis by inhibiting metal transport proteins. Finally, we consider the emergence of metal regulatory factor 1 as a drug target in diseases where it mediates zinc-induced signalling cascades leading to pathogenesis.
Topics: Animals; Chelating Agents; Drug Discovery; Homeostasis; Humans; Ionophores; Membrane Transport Proteins; Transition Elements
PubMed: 28040658
DOI: 10.1016/j.cbpa.2016.12.011 -
Marine Drugs Apr 2022This review is devoted to the study of the biological activity of polyether ionophores produced by bacteria, unicellular marine algae, red seaweeds, marine sponges, and... (Review)
Review
This review is devoted to the study of the biological activity of polyether ionophores produced by bacteria, unicellular marine algae, red seaweeds, marine sponges, and coelenterates. Biological activities have been studied experimentally in various laboratories, as well as data obtained using QSAR (Quantitative Structure-Activity Relationships) algorithms. According to the data obtained, it was shown that polyether toxins exhibit strong antibacterial, antimicrobial, antifungal, antitumor, and other activities. Along with this, it was found that natural polyether ionophores exhibit such properties as antiparasitic, antiprotozoal, cytostatic, anti-mycoplasmal, and antieczema activities. In addition, polyethers have been found to be potential regulators of lipid metabolism or inhibitors of DNA synthesis. Further study of the mechanisms of action and the search for new polyether ionophores and their derivatives may provide more effective therapeutic natural polyether ionophores for the treatment of cancer and other diseases. For some polyether ionophores, 3D graphs are presented, which demonstrate the predicted and calculated activities. The data presented in this review will be of interest to pharmacologists, chemists, practical medicine, and the pharmaceutical industry.
Topics: Anti-Bacterial Agents; Antifungal Agents; Antiprotozoal Agents; Humans; Ionophores; Neoplasms
PubMed: 35621943
DOI: 10.3390/md20050292 -
International Journal of Molecular... Jan 2023For many years, ionophores have been used to control coccidiosis in poultry. However, misuse of ionophores can cause toxicity with significant clinical symptoms. The... (Review)
Review
For many years, ionophores have been used to control coccidiosis in poultry. However, misuse of ionophores can cause toxicity with significant clinical symptoms. The most critical factors influencing ionophores' toxicity are administration dose, species, and animal age. Although clinical signs of ionophore intoxication are well studied, the toxicity mechanisms of the ionophores at the molecular level still are not fully elucidated. This review summarizes the studies focused on polyether ionophores toxicity mechanisms in animals at the clinical and molecular levels. Studies show that ionophore toxicity mainly affects myocardial and skeletal muscle cells. The molecular mechanism of the toxication could be explained by the inhibition of oxidative phosphorylation via dysregulation of ion concentration. Tiamulin-ionophore interaction and the synergetic effect of tiamulin in ionophore biotransformation are discussed. Furthermore, in recent years ionophores were candidates for reprofiling as antibacterial and anti-cancer drugs. Identifying ionophores' toxicity mechanisms at the cellular level will likely help develop novel therapies in veterinary and human medicine.
Topics: Animals; Humans; Ionophores; Anti-Bacterial Agents; Coccidiosis; Poultry
PubMed: 36675211
DOI: 10.3390/ijms24021696 -
Angewandte Chemie (International Ed. in... Jun 2022Ionophores transport ions across biological membranes and have wide-ranging applications, but a platform for their rapid development does not exist. We report a platform...
Ionophores transport ions across biological membranes and have wide-ranging applications, but a platform for their rapid development does not exist. We report a platform for developing ionophores from metal-ion chelators, which are readily available with wide-ranging affinities and specificities, and structural data that can aid rational design. Specifically, we fine-tuned the binding affinity and lipophilicity of a Zn -chelating ligand by introducing silyl groups proximal to the Zn -binding pocket, which generated ionophores that performed better than most of the currently known Zn ionophores. Furthermore, these silicon-based ionophores were specific for Zn over other metals and exhibited better antibacterial activity and less toxicity to mammalian cells than several known Zn ionophores, including pyrithione. These studies establish rational design principles for the rapid development of potent and specific ionophores and a new class of antibacterial agents.
Topics: Animals; Chelating Agents; Ionophores; Ions; Mammals; Metals; Silicon; Zinc
PubMed: 35385189
DOI: 10.1002/anie.202201698 -
MBio Dec 2018The World Health Organization reports that antibiotic-resistant pathogens represent an imminent global health disaster for the 21st century. Gram-positive superbugs...
The World Health Organization reports that antibiotic-resistant pathogens represent an imminent global health disaster for the 21st century. Gram-positive superbugs threaten to breach last-line antibiotic treatment, and the pharmaceutical industry antibiotic development pipeline is waning. Here we report the synergy between ionophore-induced physiological stress in Gram-positive bacteria and antibiotic treatment. PBT2 is a safe-for-human-use zinc ionophore that has progressed to phase 2 clinical trials for Alzheimer's and Huntington's disease treatment. In combination with zinc, PBT2 exhibits antibacterial activity and disrupts cellular homeostasis in erythromycin-resistant group A (GAS), methicillin-resistant (MRSA), and vancomycin-resistant (VRE). We were unable to select for mutants resistant to PBT2-zinc treatment. While ineffective alone against resistant bacteria, several clinically relevant antibiotics act synergistically with PBT2-zinc to enhance killing of these Gram-positive pathogens. These data represent a new paradigm whereby disruption of bacterial metal homeostasis reverses antibiotic-resistant phenotypes in a number of priority human bacterial pathogens. The rise of bacterial antibiotic resistance coupled with a reduction in new antibiotic development has placed significant burdens on global health care. Resistant bacterial pathogens such as methicillin-resistant and vancomycin-resistant are leading causes of community- and hospital-acquired infection and present a significant clinical challenge. These pathogens have acquired resistance to broad classes of antimicrobials. Furthermore, , a significant disease agent among Indigenous Australians, has now acquired resistance to several antibiotic classes. With a rise in antibiotic resistance and reduction in new antibiotic discovery, it is imperative to investigate alternative therapeutic regimens that complement the use of current antibiotic treatment strategies. As stated by the WHO Director-General, "On current trends, common diseases may become untreatable. Doctors facing patients will have to say, Sorry, there is nothing I can do for you."
Topics: Anti-Bacterial Agents; Clioquinol; Drug Resistance, Bacterial; Drug Synergism; Gram-Positive Bacteria; Ionophores; Microbial Sensitivity Tests; Zinc
PubMed: 30538186
DOI: 10.1128/mBio.02391-18 -
Biomedicine & Pharmacotherapy =... May 2021Emerging studies have shown that nigericin, an H, K and Pb ionophore, has exhibited a promising anti-cancer activity in various cancers. However, its anti-cancer... (Review)
Review
Emerging studies have shown that nigericin, an H, K and Pb ionophore, has exhibited a promising anti-cancer activity in various cancers. However, its anti-cancer mechanisms have not been fully elucidated. In this review, the recent progresses on the use of nigericin in human cancers have been summarized. By exchanging H and K across cell membranes, nigericin shows promising anti-cancer activities in in vitro and in vivo as a single agent or in combination with other anti-cancer drugs through decreasing intracellular pH (pHi). The underlying mechanisms of nigericin also include the inactivation of Wnt/β-catenin signals, blockade of Androgen Receptor (AR) signaling, and activation of Stress-Activated Protein Kinase/c-Jun N-terminal Kinase (SAPK/JNK) signaling pathways. In many cancers, nigericin is proved to specifically target putative Cancer Stem Cells (CSCs), and its synergistic effects on photodynamic therapy are also reported. Other mechanisms of nigericin including influencing the mitochondrial membrane potentials, inducing an increase in drug accumulation and autophagy, controlling insulin accumulation in nuclei, and increasing the cytotoxic activity of liposome-entrapped drugs, are also discussed. Notably, the potential adverse effects such as teratogenic effects, insulin resistance and eryptosis shall not be ignored. Taken together, these reports suggest that treatment of cancer cells with nigericin may offer a novel therapeutic strategy and future potential of translation to clinics.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Synergism; Humans; Hydrogen-Ion Concentration; Ionophores; Neoplasms; Neoplastic Stem Cells; Nigericin; Photochemotherapy; Signal Transduction
PubMed: 33508621
DOI: 10.1016/j.biopha.2021.111262 -
Chembiochem : a European Journal of... Oct 2021Several life-threatening diseases, also known as 'Channelopathies' are linked to irregularities in ion transport proteins. Significant research efforts have fostered the... (Review)
Review
Several life-threatening diseases, also known as 'Channelopathies' are linked to irregularities in ion transport proteins. Significant research efforts have fostered the development of artificial transport systems that facilitates to restore the functions of impaired natural transport proteins. Indeed, a few of these artificial ionophores demonstrate the rare combination of transmembrane ion transport and important biological activity, offering early promises of suitability in 'channel replacement therapy'. In this review, structural facets and functions of both cationophores and anionophores are discussed. Ionophores that are toxic to various bacteria and yeast, could be exploited as antimicrobial agent. Nevertheless, few non-toxic ionophores offer the likelihood of treating a wide range of genetic diseases caused by the gene mutations. In addition, their ability to disrupt cellular homeostasis and to alter lysosomal pH endow ionophores as promising candidates for cancer treatment. Overall, critically outlining the advances in artificial ionophores in terms of in vitro ion transport, possible modes of action and biological activities enables us to propose possible future roadmaps in this research area.
Topics: Bacteria; Ion Transport; Ionophores; Saccharomyces cerevisiae
PubMed: 34043277
DOI: 10.1002/cbic.202100112 -
Medical Hypotheses Dec 2020Zinc and the combination with zinc ionophore have been reported in basic research and several clinical investigations as a potentially viable and economical preventive...
Zinc and the combination with zinc ionophore have been reported in basic research and several clinical investigations as a potentially viable and economical preventive and therapeutic options for COVID-19 treatment. Zinc is a vital microelement that actively supports respiratory epithelium barrier integrity, innate and adaptive immune functions, and inflammatory regulations. Moreover, zinc may also prevent viral entry, suppress viral replication, and mitigate the damages due to oxidative stress and hyperinflammatory reaction in patients with respiratory infections. Hinokitiol (β-thujaplicin) is a natural monoterpenoid and is considered as a safe zinc ionophore to help zinc transport into cells. It has been widely used in skin and oral care, and therapeutic products for its potent antiviral, antimicrobial, antifungal, anti-inflammatory, and anticancer applications. The ongoing COVID-19 pandemic and the significant morbidity and mortality exist in the high-risk group of patients associated with other respiratory infections such as influenza, respiratory syncytial virus, and dengue fever. There is an urgent need for the development of inexpensive, safe, and effective therapeutics to prevent and treat these viral infections. Considering that hydroxychloroquine (HCQ), the most studied zinc ionophore drug for COVID-19, is linked to potentially serious side effects, we propose the implementation of hinokitiol as a zinc ionophore and anti-infective agent for the prevention and treatment of COVID-19 and other viral infections.
Topics: Anti-Infective Agents; Antiviral Agents; COVID-19; Homeostasis; Humans; Hydroxychloroquine; Ionophores; Models, Theoretical; Monoterpenes; Risk; Tropolone; Zinc; COVID-19 Drug Treatment
PubMed: 33045596
DOI: 10.1016/j.mehy.2020.110333 -
Molecules (Basel, Switzerland) Nov 2022This work is a mini-review highlighting the relevance of the θ metallabis(dicarbollide) [3,3'-Co(1,2-CBH)] with its peculiar and differentiating characteristics, among... (Review)
Review
This work is a mini-review highlighting the relevance of the θ metallabis(dicarbollide) [3,3'-Co(1,2-CBH)] with its peculiar and differentiating characteristics, among them the capacity to generate hydrogen and dihydrogen bonds, to generate micelles and vesicles, to be able to be dissolved in water or benzene, to have a wide range of redox reversible couples and many more, and to use these properties, in this case, for producing potentiometric membrane sensors to monitor amine-containing drugs or other nitrogen-containing molecules. Sensors have been produced with this monoanionic cluster [3,3'-Co(1,2-CBH)]. Other monoanionic boron clusters are also discussed, but they are much fewer. It is noteworthy that most of the electrochemical sensor species incorporate an ammonium cation and that this cation is the species to be detected. Alternatively, the detection of the borate anion itself has also been studied, but with significantly fewer examples. The functions of the borate anion in the membrane are different, even as a doping agent for polypyrrole which was the conductive ground on which the PVC membrane was deposited. Apart from these cases related to borates, the bulk of the work has been devoted to sensors in which the θ metallabis (dicarbollide) [3,3'-Co(1,2-CBH)] is the key element. The metallabis (dicarbollide) anion, [3,3'-Co(1,2-CBH)], has many applications; one of these is as new material used to prepare an ion-pair complex with bioactive protonable nitrogen containing compounds, [YH][3,3'-Co(1,2-CBH)] as an active part of PVC membrane potentiometric sensors. The developed electrodes have Nernstian responses for target analytes, i.e., antibiotics, amino acids, neurotransmitters, analgesics, for some decades of concentrations, with a short response time, around 5 s, a good stability of membrane over 45 days, and an optimal selectivity, even for optical isomers, to be used also for real sample analysis and environmental, clinical, pharmaceutical and food analysis.
Topics: Ionophores; Polymers; Hydrogen-Ion Concentration; Pyrroles; Potentiometry; Electrodes; Anions; Borates; Nitrogen; Membranes, Artificial
PubMed: 36500404
DOI: 10.3390/molecules27238312