Copper Binding by Tetrathiomolybdate Attenuates Angiogenesis and Tumor Cell Proliferation through the Inhibition of Superoxide Dismutase 1
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...
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Published in | Clinical cancer research Vol. 12; no. 16; pp. 4974 - 4982 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Philadelphia, PA
American Association for Cancer Research
15.08.2006
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-06-0171 |