Synthesis and Anticancer Properties of Water-Soluble Zinc Ionophores

Magda, Darren; Lecane, Philip; Wang, Zhong; Hu, Weilin; Thiemann, Patricia; Ma, Xuan; Dranchak, Patricia; Wang, Xiaoming; Lynch, Vincent M.; Wei, Wenhao; Csókai, Viktor; Hacia, Joseph G.; Sessler, Jonathan L.

doi:10.1158/0008-5472.can-08-0601

Cited by 85 publications

(83 citation statements)

References 20 publications

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“…In support of this, zinc administration has been shown to enhance the therapeutic indices of various antineoplastic agents (34,35). Interestingly, zinc by itself has been shown in xenograft models to be an effective antitumoral agent (36,37), as well as being implicated in the mechanism of action of novel therapies (38)(39)(40)(41). There are multiple studies suggesting that zinc addition to chemotherapeutic agents improves their antitumoral capacity, in xenograft models (20,42) as wells as in humans (43,44), and against chemoresistant cells (45).…”

Section: Discussionmentioning

confidence: 94%

Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

Arriaga

Greco

Mordoh

et al. 2014

Molecular Cancer Therapeutics

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Metallothioneins (MT) are a family of low molecular weight proteins that are silenced during colorectal cancer progression, mainly through epigenetic mechanisms, and this loss is associated with poor survival. In this article, we show that overexpression of the MT1G isoform sensitizes colorectal cell lines to the chemotherapeutic agents oxaliplatin (OXA) and 5-fluorouracil (5-FU), in part through enhancing p53 and repressing NF-kB activity. Despite being silenced, MTs can be reinduced by histone deacetylase inhibitors such as trichostatin A and sodium butyrate. In fact, this induction contributes to the cytotoxicity of these agents, given that silencing of MTs by siRNAs reduces their growth-inhibitory activities. Zinc ions also potently enhance MT expression and are cytotoxic to cancer cells. We show for the first time that OXA and 5-FU induce higher levels of intracellular labile zinc, as measured using the fluorescent probe FLUOZIN-3, and that such zinc contributes to the activation of p53 and repression of NF-kB. Addition of zinc enhanced growth inhibition by OXA and 5-FU, and was also capable of resensitizing 5-FU-resistant cell lines to levels comparable with sensitive cell lines. This effect was MT independent because silencing MTs did not affect zinc cytotoxicity. In conclusion, we show that MT induction and zinc administration are novel strategies to sensitize colorectal cancer cells to presently utilized chemotherapeutic agents. Mol Cancer Ther; 13(5); 1369-81. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 94%

Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

Arriaga

Greco

Mordoh

et al. 2014

Molecular Cancer Therapeutics

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“…When added to cells along with zinc it induced apoptosis (37)(38)(39). Although the sodium salt of pyrithione is water soluble, the zinc salt is not, prompting the synthesis and description of several water soluble derivatives designed to be used as anticancer drugs (23).…”

Section: Recognition That Some Metal-binding Compounds Act As Ionophomentioning

confidence: 99%

“…We have reported that clioquinol targets both Akt and MAP kinase pathways when inducing apoptosis of cancer cells (17,25). Magda described water soluble zinc ionophores that activate stress response pathways involving the metal-responsive transcription factor 1, the hypoxia-inducible transcription factor 1, and heat shock transcription factors (23). It is likely that additional mechanisms will be discovered, and the ability of a given drug to affect multiple pathways may determine its ultimate clinical usefulness.…”

Section: Other Mechanisms Of Actionmentioning

confidence: 99%

Metal ionophores – An emerging class of anticancer drugs

2009

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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.

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“…16 More recent studies have shown that this property can be used to kill cancer cells selectively. 17 The studies in the current report describe our attempt to characterize possible mechanisms behind this cell death process using Saccharomyces cerevisiae. Paradoxically, it was possible to increase either the sensitivity or the resistance of yeast to zinc by knocking out alternative sets of autophagy genes.…”

Section: Znmentioning

confidence: 99%