Synchrotron radiation induced X-ray emission studies of the antioxidant mechanism of the organoselenium drug ebselen

  • Jade B. Aitken
  • Peter A. Lay
  • T. T. Hong Duong
  • Roshanak Aran
  • Paul K. Witting
  • Hugh H. Harris
  • Barry Lai
  • Stefan Vogt
  • Gregory I. Giles
Original Paper

Abstract

Synchrotron radiation induced X-ray emission (SRIXE) spectroscopy was used to map the cellular uptake of the organoselenium-based antioxidant drug ebselen using differentiated ND15 cells as a neuronal model. The cellular SRIXE spectra, acquired using a hard X-ray microprobe beam (12.8-keV), showed a large enhancement of fluorescence at the Kα line for Se (11.2-keV) following treatment with ebselen (10 μM) at time periods from 60 to 240 min. Drug uptake was quantified and ebselen was shown to induce time-dependent changes in cellular elemental content that were characteristic of oxidative stress with the efflux of K, Cl, and Ca species. The SRIXE cellular Se distribution map revealed that ebselen was predominantly localized to a discreet region of the cell which, by comparison with the K and P elemental maps, is postulated to correspond to the endoplasmic reticulum. On the basis of these findings, it is hypothesized that a major outcome of ebselen redox catalysis is the induction of cellular stress. A mechanism of action of ebselen is proposed that involves the cell responding to drug-induced stress by increasing the expression of antioxidant genes. This hypothesis is supported by the observation that ebselen also regulated the homeostasis of the transition metals Mn, Cu, Fe, and Zn, with increases in transition metal uptake paralleling known induction times for the expression of antioxidant metalloenzymes.

Keywords

Antioxidant Drug Ebselen Organoselenium Synchrotron-radiation-induced X-ray emission 

Abbreviations

ARE

Antioxidant response element

ER

Endoplasmic reticulum

GPx

Glutathione peroxidase

GSH

Reduced glutathione

GSSG

Oxidized glutathione

ROS

Reactive oxygen species

SOD

Superoxide dismutase

SRIXE

Synchrotron-radiation-induced X-ray emission

References

  1. 1.
    Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T, Yasuhara H (1998) Stroke 29:12–17PubMedCrossRefGoogle Scholar
  2. 2.
    Mugesh G, du Mont WW, Sies H (2001) Chem Rev 101:2125–2179PubMedCrossRefGoogle Scholar
  3. 3.
    Giles NM, Gutowski NJ, Giles GI, Jacob C (2003) FEBS Lett 535:179–182PubMedCrossRefGoogle Scholar
  4. 4.
    Giles NM, Giles GI, Holley JE, Gutowski NJ, Jacob C (2003) Biochem Pharmacol 66:2021–2028PubMedCrossRefGoogle Scholar
  5. 5.
    Giles GI, Fry FH, Tasker KM, Holme AL, Peers C, Green KN, Klotz LO, Sies H, Jacob C (2003) Org Biomol Chem 1:4317–4322PubMedCrossRefGoogle Scholar
  6. 6.
    Giles GI, Giles NM, Collins CA, Holt K, Fry FH, Lowden PA, Gutowski NJ, Jacob C (2003) Chem Commun 2030–2031Google Scholar
  7. 7.
    Fry FH, Holme AL, Giles NM, Giles GI, Collins C, Holt K, Pariagh S, Gelbrich T, Hursthouse MB, Gutowski NJ, Jacob C (2005) Org Biomol Chem 3:2579–2587PubMedCrossRefGoogle Scholar
  8. 8.
    Giles GI, Tasker KM, Johnson RJ, Jacob C, Peers C, Green KN (2001) Chem Commun 2490–2491Google Scholar
  9. 9.
    Yamagata K, Ichinose S, Miyashita A, Tagami M (2008) Neuroscience 153:428–435PubMedCrossRefGoogle Scholar
  10. 10.
    Lapchak PA, Zivin JA (2003) Stroke 34:2013–2018PubMedCrossRefGoogle Scholar
  11. 11.
    Salom JB, Perez-Asensio FJ, Burguete MC, Marin N, Pitarch C, Torregrosa G, Romero FJ, Alborch E (2004) Eur J Pharmacol 495:55–62PubMedCrossRefGoogle Scholar
  12. 12.
    Muller A, Cadenas E, Graf P, Sies H (1984) Biochem Pharmacol 33:3235–3239PubMedCrossRefGoogle Scholar
  13. 13.
    Arthur JR (2000) Cell Mol Life Sci 57:1825–1835PubMedCrossRefGoogle Scholar
  14. 14.
    Zhao R, Holmgren A (2002) J Biol Chem 277:39456–39462PubMedCrossRefGoogle Scholar
  15. 15.
    Zhao R, Masayasu H, Holmgren A (2002) Proc Natl Acad Sci USA 99:8579–8584PubMedCrossRefGoogle Scholar
  16. 16.
    Haenen GR, De Rooij BM, Vermeulen NP, Bast A (1990) Mol Pharmacol 37:412–422PubMedGoogle Scholar
  17. 17.
    Jacob C, Maret W, Vallee BL (1998) Biochem Biophys Res Commun 248:569–573PubMedCrossRefGoogle Scholar
  18. 18.
    Xia R, Ganther HE, Egge A, Abramson JJ (2004) Biochem Pharmacol 67:2071–2079PubMedCrossRefGoogle Scholar
  19. 19.
    Blessing H, Kraus S, Heindl P, Bal W, Hartwig A (2004) Eur J Biochem 271:3190–3199PubMedCrossRefGoogle Scholar
  20. 20.
    Larabee JL, Hocker JR, Hanas JS (2009) J Inorg Biochem 103:419–426PubMedCrossRefGoogle Scholar
  21. 21.
    Sarma BK, Mugesh G (2005) J Am Chem Soc 127:11477–11485PubMedCrossRefGoogle Scholar
  22. 22.
    Sakurai T, Kanayama M, Shibata T, Itoh K, Kobayashi A, Yamamoto M, Uchida K (2006) Chem Res Toxicol 19:1196–1204PubMedCrossRefGoogle Scholar
  23. 23.
    Walther M, Holzhutter HG, Kuban RJ, Wiesner R, Rathmann J, Kuhn H (1999) Mol Pharmacol 56:196–203PubMedGoogle Scholar
  24. 24.
    Nakamura Y, Feng Q, Kumagai T, Torikai K, Ohigashi H, Osawa T, Noguchi N, Niki E, Uchida K (2002) J Biol Chem 277:2687–2694PubMedCrossRefGoogle Scholar
  25. 25.
    Zembowicz A, Hatchett RJ, Radziszewski W, Gryglewski RJ (1993) J Pharmacol Exp Ther 267:1112–1118PubMedGoogle Scholar
  26. 26.
    Cotgreave IA, Duddy SK, Kass GE, Thompson D, Moldeus P (1989) Biochem Pharmacol 38:649–656PubMedCrossRefGoogle Scholar
  27. 27.
    Tamasi V, Jeffries JM, Arteel GE, Falkner KC (2004) Arch Biochem Biophys 431:161–168PubMedCrossRefGoogle Scholar
  28. 28.
    Duvvuri M, Konkar S, Funk RS, Krise JM, Krise JP (2005) Biochemistry 44:15743–15749PubMedCrossRefGoogle Scholar
  29. 29.
    Torchilin VP (2006) Annu Rev Biomed Eng 8:343–375PubMedCrossRefGoogle Scholar
  30. 30.
    Spasojevic I, Chen Y, Noel TJ, Yu Y, Cole MP, Zhang L, Zhao Y, St Clair DK, Batinic-Haberle I (2007) Free Radic Biol Med 42:1193–1200PubMedCrossRefGoogle Scholar
  31. 31.
    Kehr S, Malinouski M, Finney L, Vogt S, Labunskyy VM, Kasaikina MV, Carlson BA, Zhou Y, Hatfield DL, Gladyshev VN (2009) J Mol Biol 389:808–818PubMedCrossRefGoogle Scholar
  32. 32.
    Aitken JB, Carter EA, Eastgate H, Hackett MJ, Harris HH, Levina A, Lee YC, Chen CI, Lai B, Vogt S, Lay PA (2010) Radiat Phys Chem 79:176–184CrossRefGoogle Scholar
  33. 33.
    Aitken JB, Levina A, Lay PA (2011) Curr Top Med Chem 11:553–571PubMedCrossRefGoogle Scholar
  34. 34.
    Carter EA, Rayner BS, McLeod AI, Wu LE, Marshall CP, Levina A, Aitken JB, Witting PK, Lai B, Cai Z, Vogt S, Lee YC, Chen CI, Tobin MJ, Harris HH, Lay PA (2010) Mol Biosyst 6:1316–1322PubMedCrossRefGoogle Scholar
  35. 35.
    Yang L, McRae R, Henary MM, Patel R, Lai B, Vogt S, Fahrni CJ (2005) Proc Natl Acad Sci USA 102:11179–11184PubMedCrossRefGoogle Scholar
  36. 36.
    Duong TTH, Witting PK, Antao ST, Parry SN, Kennerson M, Lai B, Vogt S, Lay PA, Harris HH (2009) J Neurochem 108:1143–1154PubMedCrossRefGoogle Scholar
  37. 37.
    Witting PK, Harris HH, Rayner BS, Aitken JB, Dillon CT, Stocker R, Lai B, Cai Z, Lay PA (2006) Biochemistry 45:12500–12509PubMedCrossRefGoogle Scholar
  38. 38.
    Harris HH, Levina A, Dillon CT, Mulyani I, Lai B, Cai Z, Lay PA (2005) J Biol Inorg Chem 10:105–118PubMedCrossRefGoogle Scholar
  39. 39.
    Cai Z, Lai B, Yun W, Ilinski P, Legnini D, Maser J, Rodrigues W (2000) Am Inst Phys Proc 507:472–477Google Scholar
  40. 40.
    Vogt S (2003) J Phys Paris IV 104:635–638Google Scholar
  41. 41.
    Van Espen P (2002) In: Van Grieken R, Markowicz A (eds) Handbook of X-ray spectrometry: revised and expanded. Dekker, New York, p 29Google Scholar
  42. 42.
    Waern JB, Harris HH, Lai B, Cai Z, Harding MM, Dillon CT (2005) J Biol Inorg Chem 10:443–452PubMedCrossRefGoogle Scholar
  43. 43.
    Dillon CT, Lay PA, Kennedy BJ, Stampfl AP, Cai Z, Ilinski P, Rodrigues W, Legnini DG, Lai B, Maser J (2002) J Biol Inorg Chem 7:640–645PubMedCrossRefGoogle Scholar
  44. 44.
    Yadav S, Zajac E, Singhal SS, Awasthi S (2007) Cancer Metastasis Rev 26:59–69PubMedCrossRefGoogle Scholar
  45. 45.
    Rayner B, Harris H, Carter E, Vogt S, Cai Z, Lai B, Chin C, Lee Y, Lay P, Witting P (2006) Atherosclerosis 7:S587Google Scholar
  46. 46.
    Ferreri-Jacobia M, Mak DO, Foskett JK (2005) J Biol Chem 280:3824–3831PubMedCrossRefGoogle Scholar
  47. 47.
    White JK, Stewart A, Popoff JF, Wilson S, Blackwell JM (2004) Biochem J 382:811–819PubMedCrossRefGoogle Scholar
  48. 48.
    Kruusma J, Benham AM, Williams JA, Kataky R (2006) Analyst 131:459–473PubMedCrossRefGoogle Scholar
  49. 49.
    Jung CH, Washburn MP, Wells WW (2002) Biochem Biophys Res Commun 291:550–553PubMedCrossRefGoogle Scholar
  50. 50.
    Ross MF, Prime TA, Abakumova I, James AM, Porteous CM, Smith RA, Murphy MP (2008) Biochem J 411:633–645PubMedCrossRefGoogle Scholar
  51. 51.
    Gorlach A, Klappa P, Kietzmann T (2006) Antioxid Redox Signal 8:1391–1418PubMedCrossRefGoogle Scholar
  52. 52.
    Liu Y, Kern JT, Walker JR, Johnson JA, Schultz PG, Luesch H (2007) Proc Natl Acad Sci USA 104:5205–5210PubMedCrossRefGoogle Scholar
  53. 53.
    Park EY, Rho HM (2002) Mol Cell Biochem 240:47–55PubMedCrossRefGoogle Scholar
  54. 54.
    Na HK, Kim EH, Jung JH, Lee HH, Hyun JW, Surh YJ (2008) Arch Biochem Biophys 476:171–177PubMedCrossRefGoogle Scholar
  55. 55.
    Coleman JE (1992) Annu Rev Biochem 61:897–946PubMedCrossRefGoogle Scholar
  56. 56.
    Iwasaki K, Hailemariam K, Tsuji Y (2007) J Biol Chem 282:22335–22343PubMedCrossRefGoogle Scholar
  57. 57.
    Purdom-Dickinson SE, Lin Y, Dedek M, Morrissy S, Johnson J, Chen QM (2007) J Mol Cell Cardiol 42:159–176PubMedCrossRefGoogle Scholar
  58. 58.
    Schmidt M, Zahn S, Carella M, Ohlenschlager O, Gorlach M, Kothe E, Weston J (2008) Chembiochem 9:2135–2146PubMedCrossRefGoogle Scholar

Copyright information

© SBIC 2012

Authors and Affiliations

  • Jade B. Aitken
    • 1
    • 7
    • 8
  • Peter A. Lay
    • 1
  • T. T. Hong Duong
    • 2
  • Roshanak Aran
    • 3
  • Paul K. Witting
    • 3
  • Hugh H. Harris
    • 4
  • Barry Lai
    • 5
  • Stefan Vogt
    • 5
  • Gregory I. Giles
    • 6
  1. 1.School of ChemistryThe University of SydneySydneyAustralia
  2. 2.Discipline of Neurosurgery, Australian School of Advanced MedicineMacquarie UniversitySydneyAustralia
  3. 3.Discipline of Pathology, Bosch Research Institute, Sydney Medical SchoolThe University of SydneySydneyAustralia
  4. 4.School of Chemistry and PhysicsUniversity of AdelaideAdelaideAustralia
  5. 5.X-ray Science DivisionArgonne National LaboratoryArgonneUSA
  6. 6.Department of Pharmacology and ToxicologyUniversity of OtagoDunedinNew Zealand
  7. 7.Australian SynchrotronClaytonAustralia
  8. 8.Institute of Materials Structure Science, KEKTsukubaJapan

Personalised recommendations