title: Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis.
abstract: Phosphatidylinositol-3-kinase (PI3K), and its downstream effector Akt, or protein kinase Balpha (PKBalpha), 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.
authors.affiliation: Department of Dermatology, Emory University School of Medicine, WMB 5309, 101 Woodruff Circle, Atlanta, GA 30322, USA. jarbise@emory.edu
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.forename: Tweeny
authors.initials: T
authors.lastname: Kau
authors.forename: Martha
authors.initials: M
authors.lastname: Konar
authors.forename: Krishna
authors.initials: K
authors.lastname: Narra
authors.forename: Ramani
authors.initials: R
authors.lastname: Ramchandran
authors.forename: Scott A
authors.initials: SA
authors.lastname: Summers
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Vlahos
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
authors.forename: Betsy N
authors.initials: BN
authors.lastname: Perry
authors.forename: William
authors.initials: W
authors.lastname: Matter
authors.forename: Anthony
authors.initials: A
authors.lastname: Fischl
authors.forename: James
authors.initials: J
authors.lastname: Cook
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Silver
authors.forename: Jenny
authors.initials: J
authors.lastname: Bain
authors.forename: Philip
authors.initials: P
authors.lastname: Cohen
authors.forename: David
authors.initials: D
authors.lastname: Whitmire
authors.forename: Scott
authors.initials: S
authors.lastname: Furness
authors.forename: Baskaran
authors.initials: B
authors.lastname: Govindarajan
authors.forename: J Phillip
authors.initials: JP
authors.lastname: Bowen
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001000:Ants; D002460:Cell Line; D004625:Embryo, Nonmammalian / Q000098:blood supply / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015027:Zebrafish / Q000196:embryology
chemical_list: D000470:Alkaloids; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C002351:Solenopsin A