Copper binding by tetrathiomolybdate attenuates angiogenesis and tumor cell proliferation through the inhibition of superoxide dismutase 1.
OBJECTIVE
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.


METHODS
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.
Juarez
Jose C
JC
Attenuon, LLC, San Diego, California, USA.
Betancourt
Oscar
O
Pirie-Shepherd
Steven R
SR
Guan
Xiaojun
X
Price
Melissa L
ML
Shaw
David E
DE
Mazar
Andrew P
AP
Doñate
Fernando
F
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008982:Molybdenum / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
D020533:Angiogenesis Inhibitors; C000606290:SOD1 protein, human; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3