Cell cycle arrest in cultured neuroblastoma cells exposed to a bis(thiosemicarbazonato) metal complex |
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Authors: | Laura Bica Jodi Meyerowitz Sarah J Parker Aphrodite Caragounis Tai Du Brett M Paterson Kevin J Barnham Peter J Crouch Anthony R White Paul S Donnelly |
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Institution: | (1) Department of Pathology, The University of Melbourne, Melbourne, VIC, 3010, Australia;(2) Department of Pathology, Centre for Neuroscience, The University of Melbourne, Melbourne, VIC, 3010, Australia;(3) The Mental Health Research Institute, Parkville, Melbourne, VIC, 3052, Australia;(4) Bio21 Institute of Molecular Science and Biotechnology, Parkville, Melbourne, VIC, 3052, Australia;(5) The School of Chemistry, The University of Melbourne, Melbourne, VIC, 3010, Australia; |
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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. |
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