JBIC Journal of Biological Inorganic Chemistry

, Volume 10, Issue 5, pp 443–452 | Cite as

Intracellular mapping of the distribution of metals derived from the antitumor metallocenes

  • Jenny B. Waern
  • Hugh H. Harris
  • Barry Lai
  • Zhonghou Cai
  • Margaret M. HardingEmail author
  • Carolyn T. Dillon
Original Article


The intracellular distribution of transition metals in V79 Chinese hamster lung cells treated with subtoxic doses of the organometallic anticancer complexes Cp2MCl2, where Cp is η5 -cyclopentadienyl and M is Mo, Nb, Ti, or V, has been studied by synchrotron-based X-ray fluorescence (XRF). While significantly higher concentrations of Mo and Nb were found in treated cells compared with control cells, distinct differences in the cellular distribution of each metal were observed. Analysis of thin sections of cells was consistent with some localization of Mo in the nucleus. Studies with a noncytotoxic thiol derivative of molybdocene dichloride showed an uneven distribution of Mo in the cells. For comparison, the low levels of Ti and V in cells treated with the more toxic titanocene and vanadocene complexes, respectively, resulted in metal concentrations at the detection limit of XRF. The results agree with independent chemical studies that have concluded that the biological chemistry of each of the metallocene dihalides is unique.


Molybdocene dichloride Niobocene dichloride X-ray fluorescence Cellular distribution Synchrotron-radiation-induced X-ray emission 



Atomic absorption spectroscopy




Erhlich ascites tumor


Graphite furnace atomic absorption spectroscopy


Inductively coupled plasma


Phosphate-buffered saline


Synchrotron-radiation-induced X-ray emission


X-ray fluorescence



This work was supported by the Sydney University Cancer Research Fund and the Australian Synchrotron Research Program, which is funded by the Commonwealth of Australia under the Major National Research Facilities program. The use of APS facilities was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract no. W-31-109-Eng-38. J.B.W. gratefully acknowledges the receipt of an Australian Postgraduate Award. H.H.H. acknowledges support from an Australian Synchrotron Research Program Postdoctoral Fellowship.

Supplementary material

775_2005_649_MOESM1_ESM.pdf (1 mb)
(PDF 1 MB)


  1. 1.
    Köpf-Maier P, Köpf H (1979) Angew Chem Int Ed 18:477–478Google Scholar
  2. 2.
    Köpf-Maier P, Köpf H (1979) Z Naturforsch 34b:805–807Google Scholar
  3. 3.
    Köpf-Maier P, Leitner M, Köpf H (1980) J Inorg Nucl Chem 42:1789–1791Google Scholar
  4. 4.
    Köpf-Maier P, Leitner M, Voigtländer R, Köpf H (1979) Z Naturforsch 34c:1174–1176Google Scholar
  5. 5.
    Köpf-Maier P, Köpf H (1994) In: Fricker SP (ed) Metal compounds in cancer therapy. Chapman & Hall, London, pp 109–146Google Scholar
  6. 6.
    Clarke MJ, Zhu F, Frasca DR (1999) Chem Rev 99:2511–2533Google Scholar
  7. 7.
    Berdel WE, Schmoll HJ, Scheulen ME, Korfel A, Knoche MF, Harstrci A, Bach F, Baumgart J, Sass G (1994) J Cancer Res Clin Oncol 120[Suppl]:R172Google Scholar
  8. 8.
    Christodoulou CV, Ferry DR, Fyfe DW, Young A, Doran J, Sheehan TMT, Eliopoulos A, Hale K, Baumgart J, Sass G, Kerr DJ (1998) J Clin Oncol 16:2761–2769Google Scholar
  9. 9.
    Korfel A, Scheulen ME, Schmoll HJ, Gründel O, Harstrick A, Knoche M, Fels LM, Skorzec M, Bach F, Baumgart J, Sab G, Seeber S, Thiel E, Berdel WE (1998) Clin Cancer Res 4:2701–2708Google Scholar
  10. 10.
    Lümmen G, Sperling H, Luboldt H, Otto T, Rübben H (1998) Cancer Chemother Pharmacol 42:415–417Google Scholar
  11. 11.
    Kröger N, Kleeberg UR, Mross K, Edler L, Saß G, Hossfeld DK (2000) Onkologie 23:60–62Google Scholar
  12. 12.
    Köpf-Maier P, Krahl D (1981) Naturwissenschaften 68:273–274Google Scholar
  13. 13.
    Köpf-Maier P, Krahl D (1983) Chem Biol Interact 44:317–328Google Scholar
  14. 14.
    Köpf-Maier P, Köpf H (1986) Drugs Future 11:297–320Google Scholar
  15. 15.
    Köpf-Maier P, Wagner W, Köpf H (1981) Naturwissenschaften 68:272–273Google Scholar
  16. 16.
    Harding MM, Mokdsi G (2000) Curr Med Chem 7:1289–1303Google Scholar
  17. 17.
    McLaughlin ML, Cronan Jr JM, Schaller TR, Snelling RD (1990) J Am Chem Soc 112:8949–8952Google Scholar
  18. 18.
    Zhang Z, Yang P, Guo M (1996) Transition Met Chem 21:322–326Google Scholar
  19. 19.
    Guo M, Sun H, McArdle HJ, Gambling L, Sadler PJ (2000) Biochemistry 39:10023–10033Google Scholar
  20. 20.
    Sun H, Li H, Weir RA, Sadler PJ (1998) Angew Chem Int Ed 37:1577–1579Google Scholar
  21. 21.
    Guo M, Guo Z, Sadler PJ (2001) J Biol Inorg Chem 6:698–707Google Scholar
  22. 22.
    Kuo LY, Kanatzidis MG, Sabat M, Tipton AL, Marks TJ (1991) J Am Chem Soc 113: 9027–9045Google Scholar
  23. 23.
    Balzarek C, Weakley TJR, Kuo LY, Tyler DR (2000) Organomet 19:2927–2931Google Scholar
  24. 24.
    Harding MM, Mokdsi G, Mackay JP, Prodigalidad M, Lucas SW (1998) Inorg Chem 37:2432–2437Google Scholar
  25. 25.
    Toney JH, Marks TJ (1985) J Am Chem Soc 107:947–953Google Scholar
  26. 26.
    Harding MM, Prodigalidad M, Lynch MJ (1996) J Med Chem 39:5012–5016Google Scholar
  27. 27.
    Bertsch PM, Hunter DB (2001) Chem Rev 101:1809–1842Google Scholar
  28. 28.
    Dillon CT, Lay PA, Kennedy BJ, Stampfl APJ, Cai Z, Ilinski P, Rodrigues W, Legnini DG, Lai B, Maser J (2002) J Biol Inorg Chem 7:640–645Google Scholar
  29. 29.
    Twining BS, Baines SB, Fisher NS, Maser J, Vogt S, Jacobsen C, Tovar-Sanchez A, Sanudo-Wilhelmy SA (2003) Anal Chem 75:3806–3816Google Scholar
  30. 30.
    Hall MD, Dillon CT, Zhang M, Beale P, Cai Z, Lai B, Stampfl APJ, Hambley TW (2003) J Biol Inorg Chem 8:726–732Google Scholar
  31. 31.
    Omega R, Bohic S, Tucoulou R, Somogyi A, Deves G (2004) Anal Chem 76:309–314Google Scholar
  32. 32.
    Kemner KM, Kelly SD, Lai B, Maser J, O’Loughlin EJ, Sholto-Douglas D, Cai ZH, Schneegurt MA, Kulpa CF, Nealson KH (2004) Science 306:686–687Google Scholar
  33. 33.
    Waern JB, Dillon CT, Harding MM (2005) J Med Chem 48:2093–2099Google Scholar
  34. 34.
    Vera JL, Roman FR, Melendez E (2004) Anal Bioanal Chem 379:399–403Google Scholar
  35. 35.
    Yun W, Lai B, Cai Z, Maser J, Legnini D, Gluskin E, Chen Z, Krasnoperova AA, Vladimirsky Y, Cerrina F, Di Fabrizio E, Gentili M (1999) Rev Sci Instrum 70:2238–2241Google Scholar
  36. 36.
    Lee H-R, Lai B, Yun W, Mancini D, Cai Z (1997) SPIE Proc 3149:257–264Google Scholar
  37. 37.
    Vogt S (2003) J Phys IV:Proc 104:635–638Google Scholar
  38. 38.
    Köpf-Maier P, Köpf H (1988) Struct Bonding 70:103–185Google Scholar
  39. 39.
    Mosmann T (1983) J Immunol Meth 65:55–63Google Scholar
  40. 40.
    Tada H, Shiho O, Kuroshima K-I, Koyama M, Tsukamoto K (1986) J Immunol Meth 93:157–165Google Scholar
  41. 41.
    Graphpad Software (1993) Graphpad Instat, San Diego, CAGoogle Scholar
  42. 42.
    Mokdsi G, Harding MM (2001) J Inorg Biochem 83:205–209Google Scholar

Copyright information

© SBIC 2005

Authors and Affiliations

  • Jenny B. Waern
    • 1
  • Hugh H. Harris
    • 1
  • Barry Lai
    • 3
  • Zhonghou Cai
    • 3
  • Margaret M. Harding
    • 1
    Email author
  • Carolyn T. Dillon
    • 2
  1. 1.School of ChemistryThe University of SydneySydneyAustralia
  2. 2.Department of ChemistryUniversity of WollongongWollongongAustralia
  3. 3.Experimental Facilities DivisionArgonne National LaboratoryArgonneUSA

Personalised recommendations