title: Structures and mechanisms of antitumor agents: xestoquinones uncouple cellular respiration and disrupt HIF signaling in human breast tumor cells.
abstract: The organic extract of a marine sponge, Petrosia alfiani, selectively inhibited iron chelator-induced hypoxia-inducible factor-1 (HIF-1) activation in a human breast tumor T47D cell-based reporter assay. Bioassay-guided fractionation yielded seven xestoquinones (1-7) including three new compounds: 14-hydroxymethylxestoquinone (1), 15-hydroxymethylxestoquinone (2), and 14,15-dihydroxestoquinone (3). Compounds 1-7 were evaluated for their effects on HIF-1 signaling, mitochondrial respiration, and tumor cell proliferation/viability. The known metabolites adociaquinones A (5) and B (6), which possess a 3,4-dihydro-2H-1,4-thiazine-1,1-dioxide moiety, potently and selectively inhibited iron chelator-induced HIF-1 activation in T47D cells, each with an IC(50) value of 0.2 μM. Mechanistic studies revealed that adociaquinones promote oxygen consumption without affecting mitochondrial membrane potential. Compound 1 both enhances respiration and decreases mitochondrial membrane potential, suggesting that it acts as a protonophore that uncouples mitochondrial respiration.
authors.affiliation: Department of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Du
authors.forename: Fakhri
authors.initials: F
authors.lastname: Mahdi
authors.forename: Sandipan
authors.initials: S
authors.lastname: Datta
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*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D007502:Iron Chelating Agents / Q000494:pharmacology; D008386:Marine Biology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry*; D011809:Quinones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D051793:Hypoxia-Inducible Factor 1; D007502:Iron Chelating Agents; D011809:Quinones; C068501:xestoquinone