caa a22 4500 445321040 CHVBK 20180317142704.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s10534-010-9380-7 doi (NATIONALLICENCE)springer-10.1007/s10534-010-9380-7 Cell cycle arrest in cultured neuroblastoma cells exposed to a bis(thiosemicarbazonato) metal complex [Elektronische Daten] [Laura Bica, Jodi Meyerowitz, Sarah Parker, Aphrodite Caragounis, Tai Du, Brett Paterson, Kevin Barnham, Peter Crouch, Anthony White, Paul Donnelly] 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. Springer Science+Business Media, LLC., 2010 Copper nationallicence Cell cycle nationallicence Bis(thiosemicarbazone) nationallicence Protein microarray nationallicence Bica Laura Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut Meyerowitz Jodi Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut Parker Sarah Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut Caragounis Aphrodite Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut Du Tai Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut Paterson Brett Bio21 Institute of Molecular Science and Biotechnology, Parkville, 3052, Melbourne, VIC, Australia aut Barnham Kevin Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut Crouch Peter Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut White Anthony Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut Donnelly Paul Bio21 Institute of Molecular Science and Biotechnology, Parkville, 3052, Melbourne, VIC, Australia aut BioMetals Springer Netherlands 24/1(2011-02-01), 117-133 0966-0844 24:1<117 2011 24 10534 https://doi.org/10.1007/s10534-010-9380-7 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10534-010-9380-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Bica Laura Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut NATIONALLICENCE 700 1- Meyerowitz Jodi Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut NATIONALLICENCE 700 1- Parker Sarah Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut NATIONALLICENCE 700 1- Caragounis Aphrodite Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut NATIONALLICENCE 700 1- Du Tai Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut NATIONALLICENCE 700 1- Paterson Brett Bio21 Institute of Molecular Science and Biotechnology, Parkville, 3052, Melbourne, VIC, Australia aut NATIONALLICENCE 700 1- Barnham Kevin Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut NATIONALLICENCE 700 1- Crouch Peter Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut NATIONALLICENCE 700 1- White Anthony Department of Pathology, The University of Melbourne, 3010, Melbourne, VIC, Australia aut NATIONALLICENCE 700 1- Donnelly Paul Bio21 Institute of Molecular Science and Biotechnology, Parkville, 3052, Melbourne, VIC, Australia aut NATIONALLICENCE 773 0- BioMetals Springer Netherlands 24/1(2011-02-01), 117-133 0966-0844 24:1<117 2011 24 10534 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer