PT  - JOURNAL ARTICLE
AU  - Shian, Shine-Gwo
AU  - Kao, Yu-Rung
AU  - Wu, Felicia Ying-Hsiueh
AU  - Wu, Cheng-Wen
TI  - Inhibition of Invasion and Angiogenesis by Zinc-Chelating Agent Disulfiram
AID  - 10.1124/mol.64.5.1076
DP  - 2003 Nov 01
TA  - Molecular Pharmacology
PG  - 1076--1084
VI  - 64
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/64/5/1076.short
4100  - http://molpharm.aspetjournals.org/content/64/5/1076.full
SO  - Mol Pharmacol2003 Nov 01; 64
AB  - 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 3H-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 non-cell-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.