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


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Article Info

DATE

2010-10-08

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

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. More... »

PAGES

117-133

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10534-010-9380-7

DOI

http://dx.doi.org/10.1007/s10534-010-9380-7

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1026819361

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20931265


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26 schema:description 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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35 Cu
36 D1 expression
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39 ability
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42 activity
43 alternative approach
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45 animal models
46 anticancer activity
47 anticancer effects
48 apoptosis
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50 arrest
51 brain
52 brain tumors
53 cell cycle arrest
54 cell growth
55 cell lines
56 cell sorting (FACS) analysis
57 cells
58 cellular mechanisms
59 changes
60 complexes
61 conditions
62 cultured neuroblastoma cells
63 current treatment
64 cycle arrest
65 cyclin D1 expression
66 decrease
67 development
68 development of imaging
69 diacetyl
70 drugs
71 effect
72 expression
73 factor receptor
74 features
75 fluorescent
76 gliomas
77 glyoxal
78 growth
79 growth factor receptor
80 human neuroblastoma cell line
81 hypoxic tumors
82 imaging
83 important insights
84 insights
85 insulin-like growth factor receptor
86 lines
87 mechanism
88 metal complexes
89 metal-based drugs
90 metals
91 microarray analysis
92 model
93 modulation
94 neuroblastoma
95 neuroblastoma cell growth
96 neuroblastoma cell lines
97 neuroblastoma cells
98 neurodegeneration
99 normoxic conditions
100 onset
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