Inhibition of Invasion and Angiogenesis by Zinc-Chelating Agent Disulfiram

Abstract

Cell invasion and angiogenesis are crucial processes in cancer metastasis that require extracellular matrix (ECM) degradation. Proteolytic degradation of the ECM components is a central event of invasion and angiogenesis processes. During these processes, matrix metalloproteinases (MMPs) seem to be primarily responsible for much of the ECM degradation. Disulfiram is frequently used in the treatment of alcoholism and has been reported to possess antiretroviral activity and can eject intrinsic zinc out of human immunodeficiency virus (HIV) nucleocapsid protein. In this report, we show that disulfiram inhibited invasion and angiogenesis in both tumor and endothelial cells at nontoxic concentrations. The 3 H-labeled type IV collagen degradation assay suggested that disulfiram has type IV collagenase inhibitory activity, and this inhibition was responsible for blocking invasion and angiogenesis through cell-mediated and noncell-mediated pathways. However, the mechanisms underlying cell-mediated signal pathways are not fully characterized. Our data demonstrate that the non-cell-mediated pathway is dominant. Thus, disulfiram could directly interact with MMP-2 and MMP-9 and inhibit their proteolytic activity through a zincchelating mechanism. Addition of zinc could reverse the inhibition of invasiveness and collagenase inhibition through disulfiram treatment. This finding implies that MMP-2 and MMP-9 may be the inhibitory targets for a potential disulfiram treatment. These observations raise the possibility clinical therapeutic applications for disulfiram used as a potential inhibitor of metastatic cell invasion and angiogenesis.

A Novel RING-Type Ubiquitin Ligase Breast Cancer-Associated Gene 2 Correlates with Outcome in Invasive Breast Cancer

“…Disulfiram, a drug marketed as an alcohol dehydrogenase inhibitor (Antabuse), is also known for its zinc-ejecting properties (17,18). Most recently, disulfiram was described to inhibit angiogenesis and invasion of human tumor and umbilical vein endothelial cells owing to their dependence on zinc chelating proteins.…”

“…16,17). Disulfiram was chosen because it is known as a potent, but general, zinc ejector (17,18), whereas NSC667089 very specifically inhibits the HIV type 1 nucleocapsid p7 zinc finger (16). Drug stocks (100 mmol/L) were prepared in DMSO and diluted to 100 Amol/L in 1Â ubiquitination assay reaction buffer (see above).…”

New uses for old copper-binding drugs: converting the pro-angiogenic copper to a specific cancer cell death inducer

“…It has been reported that DSF could inhibit cancer cell invasion by interacting with matrix metalloprotease 2 (MMP-2) and MMP-9 and inhibiting their proteolytic activities via chelating zinc [81]. An observation from another group suggested that antitumor activity of DSF in melanoma and hepatic tumor could be potentiated by Zn 2+ supplementation [82].…”

Metal ionophores – An emerging class of anticancer drugs

“…Why metal ionophores should selectively kill cancer cells in vivo is unclear, but the fact that they are tolerated by animals and humans is encouraging. Disulfiram, for example, a drug that is hydrolyzed into dithiocarbamates in vivo, has a long track record of safety in humans and has demonstrated anticancer and antiangiogenic activity (55,56). The cancer-specificity of these compounds may lie in their ability to alter metabolic signatures, such as NF-kappa B overexpression, that are unique to cancer cells.…”