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BioMetals

, Volume 24, Issue 1, pp 117–133 | Cite as

Cell cycle arrest in cultured neuroblastoma cells exposed to a bis(thiosemicarbazonato) metal complex

  • Laura Bica
  • Jodi Meyerowitz
  • Sarah J. Parker
  • Aphrodite Caragounis
  • Tai Du
  • Brett M. Paterson
  • Kevin J. Barnham
  • Peter J. Crouch
  • Anthony R. WhiteEmail author
  • Paul S. Donnelly
Article

Abstract

Brain tumors such as neuroblastomas and gliomas are often refractory to current treatments. Development of metal-based drugs may offer an alternative approach due to the ability to deliver radionuclides or cytotoxic metals to the tumor. Previous studies have shown that diacetyl-bis(N(4)-methylthiosemicarbazonato)-copper(II) (CuII(atsm)) can selectively target hypoxic tumors and this feature has been utilized for development of imaging and radiotherapy. However, we have recently shown that glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) (CuII(gtsm)) can target the brain in animal models of neurodegeneration. Unlike CuII(atsm), CuII(gtsm) is able to release Cu intracellularly under normoxic conditions. Glyoxal-bis(thiosemicarbazones) have reported anticancer effects but little is known about the cellular mechanisms involved. Therefore, in this study, we used protein microarray analysis to investigate the effect of CuII(gtsm) on neuroblastoma cell growth in vitro. Treatment of the human neuroblastoma cell line BE(2)-M17, resulted in cell cycle arrest as assessed by fluorescent activated cell sorting (FACS) analysis. Rapidly arrested growth was not associated with onset of apoptosis. Instead, protein microarray analysis revealed that CuII(gtsm) rapidly and potently reduced cyclin D1 expression, while increasing Kip2 expression. Other changes observed were decreased Cdk7 expression and activation of CHK2. These changes may be associated with the cell cycle arrest. We also observed a potent decrease of total and phosphorylated insulin-like growth factor receptor (IGF-IR) by CuII(gtsm) which is associated with modulation of cyclin D1 expression. Our studies reveal important insights into the potential anticancer activity of CuII(gtsm). Further studies are needed to examine the therapeutic potential of CuII(gtsm) and other bis(thiosemicarbazonato) metal complexes as metallo-drugs for treatment of systemic or brain tumors.

Keywords

Copper Cell cycle Bis(thiosemicarbazone) Protein microarray 

Notes

Acknowledgments

This work was supported by funding from the National Health and Medical Research Council of Australia and Australian Research Council. We thank Dr Anthony Purcell, Dr Dan Barr and Mr Ken Field for their help with FACS analysis.

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Laura Bica
    • 1
    • 2
    • 3
  • Jodi Meyerowitz
    • 1
    • 2
    • 3
  • Sarah J. Parker
    • 1
    • 2
    • 3
  • Aphrodite Caragounis
    • 1
    • 2
    • 3
  • Tai Du
    • 1
    • 2
    • 3
  • Brett M. Paterson
    • 4
    • 5
  • Kevin J. Barnham
    • 1
    • 3
    • 4
  • Peter J. Crouch
    • 1
    • 2
    • 3
  • Anthony R. White
    • 1
    • 2
    • 3
    Email author
  • Paul S. Donnelly
    • 4
    • 5
  1. 1.Department of PathologyThe University of MelbourneMelbourneAustralia
  2. 2.Department of PathologyCentre for Neuroscience, The University of MelbourneMelbourneAustralia
  3. 3.The Mental Health Research Institute, ParkvilleMelbourneAustralia
  4. 4.Bio21 Institute of Molecular Science and Biotechnology, ParkvilleMelbourneAustralia
  5. 5.The School of ChemistryThe University of MelbourneMelbourneAustralia

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