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Carcinogenesis Advance Access originally published online on December 8, 2006
Carcinogenesis 2007 28(5):962-967; doi:10.1093/carcin/bgl229
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Pro-angiogenesis action of arsenic and its reversal by selenium-derived compounds

Shaker A. Mousa*, Laura O'Connor, Toby G. Rossman1 and Eric Block2

The Pharmaceutical Research Institute and Albany College of Pharmacy, 9 Samaritan Road, Albany, NY 12208, USA
1 Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA
2 Department of Chemistry, University at Albany, SUNY, Albany, NY 12222, USA

* To whom correspondence should be addressed. Email: mousas{at}acp.edu

Inorganic arsenic (arsenite and arsenate) in drinking water has been associated with skin cancers and increased incidence of cardiovascular diseases. Additionally, studies have demonstrated the pro-angiogenic effect of arsenite and its potential promotion of tumor angiogenesis and tumor progression. Furthermore, recent reports demonstrated reversal of skin co-carcinogenesis by an organoselenium compound. The present study was undertaken to determine the effect and mechanism on angiogenesis of arsenite at low level and its potential reversal by various selenium-derived compounds. The pro-angiogenesis effects and mechanisms of sodium arsenite were determined using the chick chorioallantoic membrane (CAM) model over 3 days and compared with standard pro-angiogenesis factors, such as basic fibroblast growth factor (b-FGF). Additionally, the potential effect of various selenium-derived compounds—such as dimethyl selenone, diphenyl selenone, sodium selenite or Se-methyl selenocysteine—in reversing the pro-angiogenesis effect of arsenite or b-FGF was also determined in the CAM model. The pro-angiogenesis effect of arsenite or b-FGF was significantly (P < 0.01) blocked by dimethyl selenone, diphenyl selenone, sodium selenite or Se-methyl selenocysteine. The pro-angiogenesis effect of either sodium arsenite at 33 nM or b-FGF was blocked (P < 0.01) by the extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation inhibitor, PD 98059. Additionally, the pro-angiogenic effect of arsenic or b-FGF was blocked as well (P < 0.01) by the {alpha}vß3 antagonist, XT199. These data suggest that the pro-angiogenesis effect of arsenic is initiated at the plasma membrane integrin {alpha}vß3, involves activation of the ERK1/2 pathway and is effectively reversed by various selenium-derived compounds.

Abbreviations: APL, acute promyelocytic leukemia; b-FGF, basic fibroblast growth factor; CAM, chorioallantoic membrane; ERK1/2, extracellular signal-regulated kinases 1 and 2; FGF, fibroblast growth factor; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; PBS, phosphate-buffered saline; VEGF, vascular endothelial growth factor

Received May 9, 2006; revised October 11, 2006; accepted October 27, 2006.


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