Abstract
A major focus of melanoma research continues to be the search for genes/proteins that may be suitable targets for molecular therapy of primary and metastatic melanoma. In line with this effort, the objective of the study presented herein was to determine whether interfering with cell cycle progression and in particular, the expression and function of select cyclin-dependent kinases, would impair the biological features of advanced melanoma. We provide data, which document that unlike nevi and melanoma in situ, primary and metastatic melanomas express high levels of CDK2, CDK1, and CDK5. Furthermore, we present the results of in vitro and preclinical in vivo studies, which demonstrate that treatment with a small-molecule cyclin-dependent kinase inhibitor that selectively blocks the function of CDK2, CDK5, CDK1, and CDK9, leads not only to inhibition of melanoma cell proliferation and apoptosis of melanoma cells, but also impairs the growth of human melanoma xenografts.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
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CDC2 Protein Kinase / antagonists & inhibitors
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CDC2 Protein Kinase / genetics
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CDC2 Protein Kinase / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclic N-Oxides
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Cyclin-Dependent Kinase 2 / antagonists & inhibitors
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Cyclin-Dependent Kinase 2 / genetics
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Cyclin-Dependent Kinase 2 / metabolism
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Cyclin-Dependent Kinase 5 / antagonists & inhibitors
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Cyclin-Dependent Kinase 5 / genetics
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Cyclin-Dependent Kinase 5 / metabolism
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Cyclin-Dependent Kinase 9 / antagonists & inhibitors
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Cyclin-Dependent Kinase 9 / genetics
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Cyclin-Dependent Kinase 9 / metabolism
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclin-Dependent Kinases / genetics
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Cyclin-Dependent Kinases / metabolism
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Female
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Humans
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Indolizines
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Melanoma / drug therapy*
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Melanoma / enzymology
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Mice
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Mice, Nude
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Pyridinium Compounds / therapeutic use
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Transplantation, Heterologous
Substances
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Antineoplastic Agents
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Bridged Bicyclo Compounds, Heterocyclic
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Cyclic N-Oxides
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Indolizines
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Pyridinium Compounds
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dinaciclib
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Cyclin-Dependent Kinase 5
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CDC2 Protein Kinase
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CDK2 protein, human
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CDK5 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 9
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Cyclin-Dependent Kinases