title: Differential inhibition of AE1 and AE2 anion exchangers by oxonol dyes and by novel polyaminosterol analogs of the shark antibiotic squalamine.
abstract: Oxonol and polyaminosterol drugs were examined as inhibitors of recombinant mouse AE1 and AE2 anion exchangers expressed in Xenopus laevis oocytes and were compared as inhibitors of AE1-mediated anion flux in red cells and in HL-60 cells that express AE2. The oxonols WW-781, diBA(5)C4, and diBA(3)C4 inhibited HL-60 cell Cl-/Cl- exchange with IC50 values from 1 to 7 microM, 100-1000 times less potent than their IC50 values for red cell Cl-/anion exchange. In Xenopus oocytes, diBA(5)C4 inhibited AE1-mediated Cl- efflux several hundred times more potently than that mediated by AE2. Several novel squalamine-related polyaminosterols were also evaluated as anion exchange inhibitors. In contrast to diBA(5)C4, polyaminosterol 1361 inhibited oocyte-expressed AE2 8-fold more potently than AE1 (IC50 0.6 versus 5.2 microM). The 3-fold less potent desulfo-analog, 1360, showed similar preference for AE2. It was found that 1361 also partially inhibited Cl- efflux from red cells, whereas neither polyaminosterol inhibited Cl efflux from HL60 cells. Thus, the oxonol diBA(5)C4 is >100-fold more potent as an inhibitor of AE1 than of AE2, whereas the polyaminosterols 1360 and 1361 are 8-fold more potent as inhibitors of AE2 than of AE1. Assay conditions and cell type influenced IC50 values for both classes of compounds.
authors.affiliation: Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Alper
authors.forename: M N
authors.initials: MN
authors.lastname: Chernova
authors.forename: J
authors.initials: J
authors.lastname: Williams
authors.forename: M
authors.initials: M
authors.lastname: Zasloff
authors.forename: F Y
authors.initials: FY
authors.lastname: Law
authors.forename: P A
authors.initials: PA
authors.lastname: Knauf
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017920:Antiporters / Q000037:antagonists & inhibitors*; D001463:Barbiturates / Q000494:pharmacology; D027963:Chloride-Bicarbonate Antiporters; D002777:Cholestanols / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes; D005456:Fluorescent Dyes / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000494:pharmacology*; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D009865:Oocytes / Q000378:metabolism; D011073:Polyamines / Q000494:pharmacology*; D064606:SLC4A Proteins; D012754:Sharks / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology
chemical_list: D027321:Anion Transport Proteins; D000900:Anti-Bacterial Agents; D017920:Antiporters; D001463:Barbiturates; D027963:Chloride-Bicarbonate Antiporters; D002777:Cholestanols; D004095:Dihydropyridines; D005456:Fluorescent Dyes; D007555:Isoxazoles; C097374:KV 1360; D008565:Membrane Proteins; D011073:Polyamines; D064606:SLC4A Proteins; C052795:bis(1,3-dibutylbarbiturate)trimethine oxonol; C079655:squalamine