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Blood, 15 January 2007, Vol. 109, No. 2, pp. 560-565. Prepublished online as a Blood First Edition Paper on September 21, 2006; DOI 10.1182/blood-2006-06-029934. This Article Full Text (PDF) All Versions of this Article: blood-2006-06-029934v1 109/2/560    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Arbiser, J. Articles by Bowen, J P. Search for Related Content PubMed PubMed Citation Articles by Arbiser, J. Articles by Bowen, J P. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 19, 2006 Accepted August 30, 2006 Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis Jack Arbiser*, Tweeny Kau, Martha Konar, Krishna Narra, Ramani Ramchandran, Scott Summers, Chris J Vlahos, Keqiang Ye, Betsy N. Perry, William Matter, Anthony Fischl, James Cook, Pamela Silver, Jenny Bain, Philip Cohen, David Whitmire, Scott Furness, Baskaran Govindarajan, and J Phillip Bowen Dept of Dermatology, Emory University School of Medicine, Atlanta, GA Harvard Medical School & Dept of Cancer Biology, Dana Farber Cancer Institute, Boston, MA Lab of Pathology, National Cancer Institute, NIH, Rockville, MD Dept of Internal Medicine, University of Utah, Salt Lake City, UT Lilly Research Laboratories, Indianapolis, IN Dept of Biochemistry, Emory University School of Medicine, Atlanta, GA MRC Protein Phosphorylation Unit, School of Life Sciences, Dundee, Scotland Dept of Chemistry, University of Georgia, Athens, GA Dept of Chemistry & Biochemistry, University of North Carolina at Greensboro, Greensboro, NC * Corresponding author; email: jarbise{at}emory.edu. Phosphatidylinositol-3-kinase (PI3K), and its downstream effector Akt, or protein kinase B (PKB), play a major regulatory role in control of apoptosis, proliferation, and angiogenesis. PI3K and Akt are amplified or overexpressed in a number of malignancies, including sarcomas, ovarian cancer, multiple myeloma, and melanoma. This pathway regulates production of the potent angiogenic factor vascular endothelial growth factor (VEGF), and protects tumor cells against both chemotherapy and reactive oxygen-induced apoptosis through phosphorylation of substrates such as apoptotic peptidase activating factor-1 (APAF-1), forkhead proteins, and caspase 9. Given its diverse actions, compounds that suppress the PI3K/Akt pathway have potential pharmacologic utility as angiogenesis inhibitors and antineoplastic agents. Using the SVR angiogenesis assay, a screen of natural products, we isolated the alkaloid solenopsin, and found that it is a potent angiogenesis inhibitor. We also found that solenopsin inhibits the PI3K signaling pathway in cells upstream of PI3K, which may underlie its affects on angiogenesis. Consistent with inhibition of the activation of PI3K, solenopsin prevented the phosphorylation of Akt and the phosphorylation of its substrate forkhead box 01a (FOXO1a), a member of the forkhead family of transcription factors. Interestingly, solenopsin also inhibited Akt-1 activity in an ATP-competitive manner in vitro without affecting 27 of 28 other protein kinases tested. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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