Small-Molecule Screening Identifies the Selanazal Drug Ebselen as a Potent Inhibitor of DMT1-Mediated Iron Uptake

Chemistry and Biology

Volumn 13, Issue 9, 2006, Pages 965-972

  Wetli, Herbert A ^a   Buckett, Peter D ^a   Wessling Resnick, Marianne ^a  

^a HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIOXIDANT; CALCEIN; CATION TRANSPORT PROTEIN; DRUG DERIVATIVE; EBSELEN; FERRIC ION; FERROUS ION; FLUORESCEIN DERIVATIVE; MANGANESE; ORGANOSELENIUM DERIVATIVE; PROLINE; PROLINEDITHIOCARBAMATE; PYRROLE DERIVATIVE; SOLUTE CARRIER FAMILY 11 (PROTON COUPLED DIVALENT METAL ION TRANSPORTERS), MEMBER 2; SOLUTE CARRIER FAMILY 11- (PROTON-COUPLED DIVALENT METAL ION TRANSPORTERS), MEMBER 2; THIOCARBAMIC ACID DERIVATIVE;

ARTICLE; CELL LINE; DOSE RESPONSE; DRUG ANTAGONISM; DRUG EFFECT; DRUG SCREENING; GENETIC TRANSFECTION; HUMAN; IC 50; ION TRANSPORT; METABOLISM;

ANTIOXIDANTS; AZOLES; CATION TRANSPORT PROTEINS; CELL LINE; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG EVALUATION, PRECLINICAL; FERRIC COMPOUNDS; FERROUS COMPOUNDS; FLUORESCEINS; HUMANS; INHIBITORY CONCENTRATION 50; ION TRANSPORT; MANGANESE; ORGANOSELENIUM COMPOUNDS; PROLINE; THIOCARBAMATES; TRANSFECTION;

EID: 33748548397     PISSN: 10745521     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.chembiol.2006.08.005     Document Type: Article

References (35)

1. Andrews N.C. Iron homeostasis: insights from genetics and animal models. Nat. Rev. Genet. 1 (2000) 208-217
2. Donovan A., Roy C.N., and Andrews N.C. The ins and outs of iron homeostasis. Physiology (Bethesda) 21 (2006) 115-123
3. Cabantchik Z.I., Glickstein H., Milgram P., and Breuer W. A fluorescence assay for assessing chelation of intracellular iron in a membrane model system and in mammalian cells. Anal. Biochem. 233 (1996) 221-227
4. Brown J.X., Buckett P.D., and Wessling-Resnick M. Identification of small molecule inhibitors that distinguish between non-transferrin bound iron uptake and transferrin-mediated iron transport. Chem. Biol. 11 (2004) 407-416
5. Gunshin H., Fujiwara Y., Custodio A.O., Direnzo C., Robine S., and Andrews N.C. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J. Clin. Invest. 115 (2005) 1258-1266
6. Fleming M.D., Romano M.A., Su M.A., Garrick L.M., Garrick M.D., and Andrews N.C. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc. Natl. Acad. Sci. USA 95 (1998) 1148-1153
7. Fleming M.D., Trenor III C.C., Su M.A., Foernzler D., Beier D.R., Dietrich W.F., and Andrews N.C. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat. Genet. 16 (1997) 383-386
8. Gunshin H., Mackenzie B., Berger U.V., Gunshin Y., Romero M.F., Boron W.F., Nussberger S., Gollan J.L., and Hediger M.A. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388 (1997) 482-488
9. Xu H., Jin J., DeFelice L.J., Andrews N.C., and Clapham D.E. A spontaneous, recurrent mutation in divalent metal transporter-1 exposes a calcium entry pathway. PLoS Biol. 2 (2004) E50
10. Mackenzie B., and Hediger M.A. SLC11 family of H+-coupled metal-ion transporters NRAMP1 and DMT1. Pflugers Arch. 447 (2004) 571-579
11. Ogawa A., Yoshimoto T., Kikuchi H., Sano K., Saito I., Yamaguchi T., and Yasuhara H. Ebselen in acute middle cerebral artery occlusion: a placebo-controlled, double-blind clinical trial. Cerebrovasc. Dis. 9 (1999) 112-118
12. Yamaguchi T., Sano K., Takakura K., Saito I., Shinohara Y., Asano T., and Yasuhara H. Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Stroke 29 (1998) 12-17
13. Saito I., Asano T., Sano K., Takakura K., Abe H., Yoshimoto T., Kikuchi H., Ohta T., and Ishibashi S. Neuroprotective effect of an antioxidant, ebselen, in patients with delayed neurological deficits after aneurysmal subarachnoid hemorrhage. Neurosurgery 42 (1998) 269-277
14. Su M.A., Trenor C.C., Fleming J.C., Fleming M.D., and Andrews N.C. The G185R mutation disrupts function of the iron transporter Nramp2. Blood 92 (1998) 2157-2163
15. Davis M.T., and Bartfay W.J. Ebselen decreases oxygen free radical production and iron concentrations in the hearts of chronically iron-overloaded mice. Biol. Res. Nurs. 6 (2004) 37-45
16. Inman R.S., and Wessling-Resnick M. Characterization of transferrin-independent iron transport in K562 cells. Unique properties provide evidence for multiple pathways of iron uptake. J. Biol. Chem. 268 (1993) 8521-8528
17. Zhao R., and Holmgren A. Ebselen is a dehydroascorbate reductase mimic, facilitating the recycling of ascorbate via mammalian thioredoxin systems. Antioxid. Redox Signal. 6 (2004) 99-104
18. Schewe T. Molecular actions of ebselen-an antiinflammatory antioxidant. Gen. Pharmacol. 26 (1995) 1153-1169
19. Borges V.C., Rocha J.B., and Nogueira C.W. Effect of diphenyl diselenide, diphenyl ditelluride and ebselen on cerebral Na(+), K(+)-ATPase activity in rats. Toxicology 215 (2005) 191-197
20. Weber C., Erl W., Pietsch A., Strobel M., Ziegler-Heitbrock H.W., and Weber P.C. Antioxidants inhibit monocyte adhesion by suppressing nuclear factor-κ B mobilization and induction of vascular cell adhesion molecule-1 in endothelial cells stimulated to generate radicals. Arterioscler. Thromb. 14 (1994) 1665-1673
21. Gupta S., Young D., and Sen S. Inhibition of NF-κB induces regression of cardiac hypertrophy, independent of blood pressure control, in spontaneously hypertensive rats. Am. J. Physiol. Heart Circ. Physiol. 289 (2005) H20-H29
22. Flohe L., Brigelius-Flohe R., Saliou C., Traber M.G., and Packer L. Redox regulation of NF-κB activation. Free Radic. Biol. Med. 28 (1997) 1115-1126
23. Massa F., Storr M., and Lutz B. The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract. J. Mol. Med. 83 (2005) 944-954
24. Demuth D.G., and Molleman A. Cannabinoid signalling. Life Sci. 78 (2006) 549-563
25. Zhao R., Masayasu H., and Holmgren A. Ebselen: a substrate for human thioredoxin reductase strongly stimulating its hydroperoxide reductase activity and a superfast thioredoxin oxidant. Proc. Natl. Acad. Sci. USA 99 (2002) 8579-8584
26. Zhao R., and Holmgren A. A novel antioxidant mechanism of ebselen involving ebselen diselenide, a substrate of mammalian thioredoxin and thioredoxin reductase. J. Biol. Chem. 277 (2002) 39456-39462
27. Selim M.H., and Ratan R.R. The role of iron neurotoxicity in ischemic stroke. Ageing Res. Rev. 3 (2004) 345-353
28. Marciani P., Trotti D., Hediger M.A., and Monticelli G. Modulation of DMT1 activity by redox compounds. J. Membr. Biol. 197 (2004) 91-99
29. Esposito B.P., Epsztejn S., Breuer W., and Cabantchik Z.I. A review of fluorescence methods for assessing labile iron in cells and biological fluids. Anal. Biochem. 304 (2002) 1-18
30. Petrat F., de Groot H., Sustmann R., and Rauen U. The chelatable iron pool in living cells: a methodically defined quantity. Biol. Chem. 383 (2002) 489-502
31. Petrat F., Paluch S., Dogruoz E., Dorfler P., Kirsch M., Korth H.G., Sustmann R., and de Groot H. Reduction of Fe(III) ions complexed to physiological ligands by lipoyl dehydrogenase and other flavoenzymes in vitro: implications for an enzymatic reduction of Fe(III) ions of the labile iron pool. J. Biol. Chem. 278 (2003) 46403-46413
32. MacKenzie B., Ujwal M.L., Chang M.-H., Romero M.F., and Hediger M.A. Divalent metal-ion transporter DMT1 mediates both H+-coupled Fe2+ transport and uncoupled fluxes. Pflugers Arch-Eur J Physiol 451 (2006) 544-558
33. Napier I., Ponka P., and Richardson D.R. Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood 105 (2005) 1867-1874
34. O'Halloran T.V., and Culotta V.C. Metallochaperones, an intracellular shuttle service for metal ions. J. Biol. Chem. 275 (2000) 25057-25060
35. Bradford M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72 (1976) 248-254