title: Molecular-targeted antitumor agents. 19. Furospongolide from a marine Lendenfeldia sp. sponge inhibits hypoxia-inducible factor-1 activation in breast tumor cells.
abstract: A natural product chemistry-based approach was employed to discover small-molecule inhibitors of the important tumor-selective molecular target hypoxia-inducible factor-1 (HIF-1). Bioassay-guided isolation of an active lipid extract of a Saipan collection of the marine sponge Lendenfeldia sp. afforded the terpene-derived furanolipid furospongolide as the primary inhibitor of hypoxia-induced HIF-1 activation (IC(50) 2.9 μM, T47D breast tumor cells). The active component of the extract also contained one new cytotoxic scalarane sesterterpene and two previously reported scalaranes. Furospongolide blocked the induction of the downstream HIF-1 target secreted vascular endothelial growth factor (VEGF) and was shown to suppress HIF-1 activation by inhibiting the hypoxic induction of HIF-1α protein. Mechanistic studies indicate that furospongolide inhibits HIF-1 activity primarily by suppressing tumor cell respiration via the blockade of NADH-ubiquinone oxidoreductase (complex I)-mediated mitochondrial electron transfer.
authors.affiliation: Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Shui-Chun
authors.initials: SC
authors.lastname: Mao
authors.forename: J Brian
authors.initials: JB
authors.lastname: Morgan
authors.forename: Mika B
authors.initials: MB
authors.lastname: Jekabsons
authors.forename: Yu-Dong
authors.initials: YD
authors.lastname: Zhou
authors.forename: Dale G
authors.initials: DG
authors.lastname: Nagle
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005663:Furans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D008386:Marine Biology; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C562263:furospongolide