The cytotoxic mechanisms of disulfiram and copper(ii) in cancer cells

Tawari, Patricia Erebi; Wang, Zhipeng; Najlah, Mohammad; Tsang, Chi; Kannappan, Vinodh; Liu, Peng; McConville, Christopher; He, Bin; Armesilla, Ángel Luis; Wang, Weiguang

doi:10.1039/c5tx00210a

Cited by 74 publications

(76 citation statements)

References 21 publications

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“…DS is highly cytotoxic in several types of cancer cells in vitro ,6, 10, 15, 16, 30, 31, 32 whereas oral administration of free DS does not inhibit tumor growth in vivo 33 . Recent publication suggests that the intact sulfhydryl group is essential for the anticancer function of DS 22, 24. The degradation of DS in the bloodstream destroys the sulfhydryl group making DS lose its cancer targeting ability.…”

Section: Discussionmentioning

confidence: 99%

“…The anticancer activity of DS is copper (Cu), zinc and some other divalent transitional metal elements dependent 11, 20, 21, 22. DS is quickly reduced to diethyldithiocarbamate (DDC), a strong chelator of copper(II).…”

mentioning

confidence: 99%

“…The reaction between DDC and Cu(II) generates ROS which are highly toxic to cancer cells. Due to the extremely short lifespan of ROS in human tissues, 23 the extracellular ROS can target cancer cells only when the reaction takes place within the cancer tissues 22, 24. DDC-Cu, the final product of the DS and Cu reaction, can also penetrate into cancer cells and induce apoptosis 22 .…”

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confidence: 99%

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Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells

Wang

Tan

McConville

et al. 2017

Nanomedicine: Nanotechnology, Biology and Medicine

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Disulfiram (DS), an anti-alcoholism drug, shows very strong cytotoxicity in many cancer types. However its clinical application in cancer treatment is limited by the very short half-life in the bloodstream. In this study, we developed a poly lactic-co-glycolic acid (PLGA)-encapsulated DS protecting DS from the degradation in the bloodstream. The newly developed DS-PLGA was characterized. The DS-PLGA has very satisfactory encapsulation efficiency, drug-loading content and controlled release rate in vitro. PLGA encapsulation extended the half-life of DS from shorter than 2 minutes to 7 hours in serum. In combination with copper, DS-PLGA significantly inhibited the liver cancer stem cell population. CI-isobologram showed a remarkable synergistic cytotoxicity between DS-PLGA and 5-FU or sorafenib. It also demonstrated very promising anticancer efficacy and antimetastatic effect in liver cancer mouse model. Both DS and PLGA are FDA approved products for clinical application. Our study may lead to repositioning of DS into liver cancer treatment.

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Section: Discussionmentioning

confidence: 99%

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Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells

Wang

Tan

McConville

et al. 2017

Nanomedicine: Nanotechnology, Biology and Medicine

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“…Previously Tawari et al noted an increase in ROS when DSF and copper were added to cell media but not when DDC and copper were added. 20 The authors suggested that ROS generation was a by-product produced that occurred when DSF and Cu were mixed in vitro. However, ROS would not be generated if using preformed Cu(DDC) 2 complex in liposomes, as done in the studies reported here.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests clearly that the copper complex of DDC is the therapeutically active agent. 19,20 Cvek et al have shown that Cu(DDC) 2 acts as a proteosome inhibitor, 21 specifically through binding to the 19S lid of the proteosome rather than the 20S subunit, which is targeted by bortezomib. 22 Before developing any therapeutic application for Cu(DDC) 2 , there are formulation issues that need to be addressed if its use in vivo is to be evaluated.…”

Section: Introductionmentioning

confidence: 99%

Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent

Wehbe¹,

Anantha²,

Shi³

et al. 2017

IJN

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Copper diethyldithiocarbamate (Cu(DDC) 2 ) is the active anticancer agent generated when disulfiram (DSF) is provided in the presence of copper. To date, research directed toward repurposing DSF as an anticancer drug has focused on administration of DSF and copper in combination, efforts that have proven unsuccessful in clinical trials. This is likely due to the inability to form Cu(DDC) 2 at relevant concentrations in regions of tumor growth. Little effort has been directed toward the development of Cu(DDC) 2 because of the inherent aqueous insolubility of the complex. Here, we describe an injectable Cu(DDC) 2 formulation prepared through a method that involves synthesis of Cu(DDC) 2 inside the aqueous core of liposomes. Convection-enhanced delivery of a Cu(DDC) 2 formulation prepared using 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/cholesterol liposomes into a rat model of F98 glioma engendered a 25% increase in median survival time relative to vehicle-treated animals. In a murine subcutaneous MV-4–11 model, treatment resulted in a 45% reduction in tumor burden when compared to controls. Pharmacokinetic studies indicated that the Cu(DDC) 2 was rapidly eliminated after intravenous administration while the liposomes remained in circulation. To test whether liposomal lipid composition could increase Cu(DDC) 2 circulation lifetime, a number of different formulations were evaluated. Studies demonstrated that liposomes composed of DSPC and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-(carboxy[polyethylene glycol]-2000) (95:5) enhanced Cu(DDC) 2 concentrations in the circulation as reflected by a 4.2-fold increase in plasma AUC (0−∞) relative to the DSPC/cholesterol formulation. The anticancer activity of this Cu(DDC) 2 formulation was subsequently evaluated in the MV-4–11 model. At its maximum tolerated dose, this formulation exhibited comparable activity to the DSPC/cholesterol formulation. This is the first report demonstrating the therapeutic effects of an injectable Cu(DDC) 2 formulation in vivo.

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Developing Ligands to Target Transition Metals in Cancer

Utterback

Tomat

2019

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Transition metals are essential for the function for numerous metalloproteins and cofactors in living systems. Their acquisition, transport, and storage are tightly regulated and the homeostasis of redox‐active cations such as iron and copper is especially critical to prevent the damaging effects of oxidative stress. Indeed the dyshomeostasis of metals has been observed in the pathophysiology of several diseases, and multiple metal‐binding compounds are currently under investigation as therapeutic candidates. Herein, we focus on the altered metal metabolisms of malignant cells and on metal‐binding strategies for the design of cancer chemotherapeutics. Iron, copper, and zinc chelators with a variety of binding motifs have been studied for their antiproliferative effects in malignant cells, and several compounds have reached clinical trials. Recent pro‐chelation approaches, in which the chelator is activated under specific conditions, are poised to increase therapeutic indexes and avoid unwanted side effects. As additional information emerges on the roles of metals in cancer biology, the design of metal‐binding drug candidates is evolving to improve their selectivity and efficacy and to consider their effects on the immune cells present in the tumor microenvironment. In addition, extensive studies to develop inhibitors of metalloenzymes relevant to cancer growth have led to several new anticancer therapeutics that coordinate the zinc centers in the active site of the enzymes. As illustrated by the examples collected herein, approaches that target either labile or protein‐bound transition metals have significant potential to produce new therapeutic options for cancer treatment.

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The cytotoxic mechanisms of disulfiram and copper(ii) in cancer cells

Abstract: The anticancer activity of disulfiram (DS) is copper(ii) (Cu)-dependent.

Cited by 74 publications

References 21 publications

Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells

Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells

Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent

Developing Ligands to Target Transition Metals in Cancer

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