Metal ionophores – An emerging class of anticancer drugs

Abstract

SummaryCompounds that bind metals such as copper and zinc have many biological activities, including the ability to induce apoptosis in cancer cells. Although some of these compounds have been considered to act as chelators of metals, decreasing their bioavailability, others increase intracellular metal concentrations. We review recent work regarding the recognition of the biological effects of metal ionophores with different structures, particularly with regard to their actions upon cancer cells focusing on dithiocarbamates, pyrithione, and the 8-hydroxyquinoline derivative, clioquinol. We provide a biologically based classification of metal-binding compounds that allows an experimental distinction between chelators and ionophores that can be readily used by biologists, which may lead to further study and classification of metal-binding drugs. Metal ionophores may kill cancer cells by a number of mechanisms, including lysosomal disruption and proteasome inhibition, and likely others. Because some of these compounds have been safely administered to animals and humans, they have the potential to become clinically useful anticancer agents.

Copper signaling in the brain and beyond

“…The choice of chelator is critical: on short time-scales (<1 hr), membrane-impermeable chelators deplete only extracellular copper and copper that may be rapidly moving through release-and-uptake cycles, while membrane-permeable chelators can access both intra-and extracellular copper, as well as potentially form ternary complexes with copper chaperones (15), preventing copper trafficking or mobilization. Additionally, copper ionophores, such as clioquinol and other 8-hydroxyquinoline (8HQ) derivatives, redistribute copper across cell and organelle membranes, altering the labile copper pool without adding or removing copper from the system (16,17). Changes to the labile copper pool may be assessed by the use of fluorescent small-molecule indicators that can equilibrate with kinetically accessible copper in the cytosol, enabling one to distinuguish labile copper from total copper, the latter of which is typically measured using direct techniques including X-ray fluorescence microscopy (XFM) or mass spectrometry imaging (14,18).…”

Parameters Influencing Zinc in Experimental Systems in Vivo and in Vitro

“…TPEN is usually used to generate the depleted sample for the determination of the autofluorescence, and zinc is used in combination with pyrithione to measure the maximum fluorescence [16]. Pyrithione is an ionophore that transports zinc, copper and lead across biological membranes [42]. Given in combination with zinc, it is able to induce apoptosis by facilitated intracellular zinc uptake, resulting in toxic intracellular zinc concentrations [43].…”

Zinc at Cytotoxic Concentrations Affects Posttranscriptional Events of Gene Expression in Cancer Cells

“…We previously reported that clioquinol acts as a zinc ionophore in Raji [18], DU-145 [19], and MCF-7 cells [26]. Treatment with zinc alone did not increase intracellular zinc levels in MCF-7 cells [26].…”