Copper Binding by Tetrathiomolybdate Attenuates Angiogenesis and Tumor Cell Proliferation through the Inhibition of Superoxide Dismutase 1

• Published in: Clinical cancer research Vol. 12; no. 16; pp. 4974 - 4982
• Main Authors: Jose C. Juarez, Oscar Betancourt, Jr, Steven R. Pirie-Shepherd, Xiaojun Guan, Melissa L. Price, David E. Shaw, Andrew P. Mazar, Fernando Doñate
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.2006
• Subjects: Angiogenesis Inhibitors - pharmacology; angiogenesis inhibitors: endogenous and synthetic; Antineoplastic agents; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; cell growth/signaling pathways; Cell Proliferation - drug effects; Copper - metabolism; Endothelial Cells - drug effects; Endothelial Cells - enzymology; experimental and molecular therapeutics; Humans; Medical sciences; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Molybdenum - pharmacology; Multiple Myeloma - blood supply; Multiple Myeloma - drug therapy; Multiple Myeloma - enzymology; Multiple Myeloma - pathology; new targets; Pharmacology. Drug treatments; Phosphorylation - drug effects; signal transduction; Superoxide Dismutase - antagonists & inhibitors; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Cell proliferation; Angiogenesis; Enzyme; Superoxide dismutase; Inhibitor; Oxidoreductases; Neovascularization; Copper; Tumor cell
• DOI: 10.1158/1078-0432.CCR-06-0171
• ISSN: 1078-0432

Purpose: A second-generation tetrathiomolybdate analogue (ATN-224; choline tetrathiomolybdate), which selectively binds copper with high affinity, is currently completing two phase I clinical trials in patients with advanced solid and advanced hematologic malignancies. However, there is very little information about the mechanism of action of ATN-224 at the molecular level. Experimental Design: The effects of ATN-224 on endothelial and tumor cell growth were evaluated in cell culture experiments in vitro . The antiangiogenic activity of ATN-224 was investigated using the Matrigel plug model of angiogenesis. Results: ATN-224 inhibits superoxide dismutase 1 (SOD1) in tumor and endothelial cells. The inhibition of SOD1 leads to inhibition of endothelial cell proliferation in vitro and attenuation of angiogenesis in vivo . The inhibition of SOD1 activity in endothelial cells is dose and time dependent and leads to an increase in the steady-state levels of superoxide anions, resulting in the inhibition of extracellular signal-regulated kinase phosphorylation without apparent induction of apoptosis. In contrast, the inhibition of SOD1 in tumor cells leads to the induction of apoptosis. The effects of ATN-224 on endothelial and tumor cells could be substantially reversed using Mn(III)tetrakis(4-benzoic acid)porphyrin chloride, a catalytic small-molecule SOD mimetic. Conclusions: These data provide a distinct molecular target for the activity of ATN-224 and provide validation for SOD1 as a target for the inhibition of angiogenesis and tumor growth.