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ToxSci Advance Access originally published online on May 11, 2005
Toxicological Sciences 2005 86(2):248-257; doi:10.1093/toxsci/kfi190
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Role of HIF Signaling on Tumorigenesis in Response to Chronic Low-Dose Arsenic Administration

Chandrashekhar D. Kamat*,1, Dixy E. Green*,1, Susan Curilla*, Linda Warnke*, Joshua W. Hamilton{dagger}, Stefan Sturup{dagger}, Callie Clark* and Michael A. Ihnat*,2

* Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190, and {dagger} Center for Environmental Health Sciences and Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755

Received March 30, 2005; accepted April 28, 2005

Trivalent inorganic arsenic (arsenite, arsenic trioxide, As(III)) is a primary contaminant of groundwater supplies worldwide. As(III), marketed as trisenox, is also an FDA-approved agent to treat cancer It has been previously shown by our laboratory that As(III) administered at doses lower than a therapeutic anticancer dose results in an increase in tumor formation and blood vessel density of tumors. In this work it was found that chronic administration of As(III) approaching the EPA action level of 10 ppb, given in the drinking water of mice 5 weeks prior to B16-F10 melanoma implantation, increased the growth rate of primary tumors and the number of metastases to the lung. Further, levels of arsenic in the tumor and lung were found to be much greater than those in the blood and similar to pro-angiogenic As(III) doses. Levels of hypoxia inducible factor-1{alpha} (HIF-1{alpha}) and vascular endothelial growth factor (VEGF) surrounding the blood vessels in the tumors of the As(III)-treated mice were also found to be increased. Exposure of isolated B16-F10 tumor cells to chronic (3 or 7 day) but not acute (4 h) low-dose As(III) was found to increase HIF-1{alpha} expression and secretion of VEGF. Finally, coadministration of an inhibitor of HIF (YC-1) or a VEGFR-2 kinase inhibitor (SU5416) was found to antagonize the pro-angiogenic effects of low-dose As(III). Together, these results suggest that chronic exposure to low-dose As(III) could stimulate growth of tumors through a HIF-dependent stimulation of angiogenesis.

Key Words: arsenic; angiogenesis; hypoxia inducible factor; vascular endothelial growth factor; tumorigenesis.


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