Skip Navigation


ToxSci Advance Access originally published online on May 11, 2005
Toxicological Sciences 2005 86(2):248-257; doi:10.1093/toxsci/kfi190
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
86/2/248    most recent
kfi190v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (14)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Kamat, C. D.
Right arrow Articles by Ihnat, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kamat, C. D.
Right arrow Articles by Ihnat, M. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Am. J. Pathol.Home page
A. C. Straub, L. R. Klei, D. B. Stolz, and A. Barchowsky
Arsenic Requires Sphingosine-1-Phosphate Type 1 Receptors to Induce Angiogenic Genes and Endothelial Cell Remodeling
Am. J. Pathol., May 1, 2009; 174(5): 1949 - 1958.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
M. Kaczmarek, R. E. Cachau, I. A. Topol, K. S. Kasprzak, A. Ghio, and K. Salnikow
Metal Ions-Stimulated Iron Oxidation in Hydroxylases Facilitates Stabilization of HIF-1{alpha} Protein
Toxicol. Sci., February 1, 2009; 107(2): 394 - 403.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
A. M. Hays, R. C. Lantz, L. S. Rodgers, J. J. Sollome, R. R. Vaillancourt, A. S. Andrew, J. W. Hamilton, and T. D. Camenisch
Arsenic-Induced Decreases in the Vascular Matrix
Toxicol Pathol, October 1, 2008; 36(6): 805 - 817.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
W. C. Prozialeck, J. R. Edwards, D. W. Nebert, J. M. Woods, A. Barchowsky, and W. D. Atchison
The Vascular System as a Target of Metal Toxicity
Toxicol. Sci., April 1, 2008; 102(2): 207 - 218.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
L. R. Klei and A. Barchowsky
Positive Signaling Interactions between Arsenic and Ethanol for Angiogenic Gene Induction in Human Microvascular Endothelial Cells
Toxicol. Sci., April 1, 2008; 102(2): 319 - 327.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. R. Shaw, K. Gabor, E. Hand, A. Lankowski, L. Durant, R. Thibodeau, C. R. Stanton, R. Barnaby, B. Coutermarsh, K. H. Karlson, et al.
Role of glucocorticoid receptor in acclimation of killifish (Fundulus heteroclitus) to seawater and effects of arsenic
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R1052 - R1060.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
M. Lopez-Lazaro
HIF-1: hypoxia-inducible factor or dysoxia-inducible factor?
FASEB J, May 1, 2006; 20(7): 828 - 832.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.