Biomedical applications of copper ionophores

Oliveri, Valentina

doi:10.1016/j.ccr.2020.213474

Cited by 106 publications

(68 citation statements)

References 239 publications

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“…In a physiological environment, competition phenomena are often recorded due to the possibility that either endogenous substances can compete with the therapeutic metal binding compound, or different metals within the body can compete for interaction with the bioactive molecule [46] . Furthermore, it should be considered that most of the metal‐binding compounds possess a Brønsted base character, making them highly sensitive to pH variation, with great implications for the treatment of several pathological conditions [53] . Due to the integration of copper ions into multiple cellular pathways, both copper chelators and ionophores showed promising effects in cancer treatment [54] .…”

Section: Coppermentioning

confidence: 99%

Copper: An Intracellular Achilles’ Heel Allowing the Targeting of Epigenetics, Kinase Pathways, and Cell Metabolism in Cancer Therapeutics

et al. 2021

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Copper is an essential transition metal frequently increased in cancer known to strongly influence essential cellular processes. Targeted therapy protocols utilizing both novel and repurposed drug agents initially demonstrate strong efficacy, before failing in advanced cancers as drug resistance develops and relapse occurs. Overcoming this limitation involves the development of strategies and protocols aimed at a wider targeting of the underlying molecular changes. Receptor Tyrosine Kinase signaling pathways, epigenetic mechanisms and cell metabolism are among the most common therapeutic targets, with molecular investigations increasingly demonstrating the strong influence each mechanism exerts on the others. Interestingly, all these mechanisms can be influenced by intracellular copper. We propose that copper chelating agents, already in clinical trial for multiple cancers, may simultaneously target these mechanisms across a wide variety of cancers, serving as an excellent candidate for targeted combination therapy. This review summarizes the known links between these mechanisms, copper, and copper chelation therapy.

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Section: Coppermentioning

confidence: 99%

Copper: An Intracellular Achilles’ Heel Allowing the Targeting of Epigenetics, Kinase Pathways, and Cell Metabolism in Cancer Therapeutics

et al. 2021

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“…[ 1–3 ] Apart from the essential roles played by copper in the human body, copper‐catalyzed redox reactions generate reactive oxygen species that destroy biomolecules like lipids, proteins, and DNA, and therefore, have been utilized to design drugs. [ 4,5 ] The decomposition of hydrogen peroxide (a) is a feasible copper‐catalyzed redox reaction employed in drug design because it generates highly reactive hydroxyl radicals via a Fenton‐like reaction, i.e., the reduction of hydrogen peroxides with copper(I) (Scheme 1a,i). [ 5,6 ] The generated hydroxyl radical finds application not only in the field of organic chemistry, but also in drug discovery research due to its anticancer and antibacterial effects.…”

Section: Introductionmentioning

confidence: 99%

Accelerated Redox Reaction of Hydrogen Peroxide by Employing Locally Concentrated State of Copper Catalysts on Polymer Chain

Osawa

Kitanishi

Kiuchi

et al. 2021

Macromol. Rapid Commun.

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Copper complexes act as catalysts for redox reactions to generate reactive oxygen species that destroy biomolecules and, therefore, are utilized to design drugs including antitumor and antibacterial medicines. Especially, catalytic reaction for hydrogen peroxide decomposition is important because it includes the process for generating highly toxic hydroxyl radical, i.e., Fenton‐like reaction. Considering that multicoppers/hydrogen peroxide species are the important intermediates for the redox reaction, herein a polymer having copper complexes in the side chains is designed to facilitate the formation of the intermediates by building locally concentrated state of the copper complexes. The polymer increases their catalytic activities for hydrogen peroxide decomposition and promotes reactive oxygen species’ generation, eventually leading to higher antibacterial activity. This reveals the virtue of building a locally concentrated state of catalysts on polymers toward drug design with low amounts of transition metals.

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“…Pyrithione is a bidentate metal-binding agent that forms neutral, lipophilic metal complexes with divalent and trivalent metal ions [ 36 ]. These properties, and its ability to facilitate intracellular metal accumulation, categorise pyrithione as an ionophore, to distinguish its biological activity from metal chelators that sequester or deplete cellular metals [ 37 ]. The antimicrobial activity of pyrithione, even in its complexed form with Zn(II), is associated with its copper ionophore activity [ 34 , 35 , 38 , 39 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

Membrane Transporters Involved in the Antimicrobial Activities of Pyrithione in Escherichia coli

et al. 2021

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Pyrithione (2-mercaptopyridine-N-oxide) is a metal binding modified pyridine, the antibacterial activity of which was described over 60 years ago. The formulation of zinc-pyrithione is commonly used in the topical treatment of certain dermatological conditions. However, the characterisation of the cellular uptake of pyrithione has not been elucidated, although an unsubstantiated assumption has persisted that pyrithione and/or its metal complexes undergo a passive diffusion through cell membranes. Here, we have profiled specific membrane transporters from an unbiased interrogation of 532 E. coli strains of knockouts of genes encoding membrane proteins from the Keio collection. Two membrane transporters, FepC and MetQ, seemed involved in the uptake of pyrithione and its cognate metal complexes with copper, iron, and zinc. Additionally, the phenotypes displayed by CopA and ZntA knockouts suggested that these two metal effluxers drive the extrusion from the bacterial cell of potentially toxic levels of copper, and perhaps zinc, which hyperaccumulate as a function of pyrithione. The involvement of these distinct membrane transporters contributes to the understanding of the mechanisms of action of pyrithione specifically and highlights, more generally, the important role that membrane transporters play in facilitating the uptake of drugs, including metal–drug compounds.

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Biomedical applications of copper ionophores

Cited by 106 publications

References 239 publications

Copper: An Intracellular Achilles’ Heel Allowing the Targeting of Epigenetics, Kinase Pathways, and Cell Metabolism in Cancer Therapeutics

Copper: An Intracellular Achilles’ Heel Allowing the Targeting of Epigenetics, Kinase Pathways, and Cell Metabolism in Cancer Therapeutics

Accelerated Redox Reaction of Hydrogen Peroxide by Employing Locally Concentrated State of Copper Catalysts on Polymer Chain

Membrane Transporters Involved in the Antimicrobial Activities of Pyrithione in Escherichia coli

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