Abstract
The aurora kinases facilitate transit from G2 through cytokinesis and, thus, are targets in cancer therapy. Multiple myeloma (MM) is a malignancy characterized by genetic instability, suggesting a disruption of checkpoints that arrest cells at G2M when injury to the mitotic machinery occurs. Since deficient checkpoints would prevent cell cycle arrest and may render cells susceptible to apoptosis in mitosis and since aurora kinases are intermediaries in checkpoint pathways, we tested antimyeloma effects of 2 agents that inhibit aurora kinases. Both inhibited growth of MM lines and primary myeloma samples at nanomolar concentrations while having less of an effect on proliferating lymphocytes and hematopoietic cells. MM cells were not protected by IL-6 or activating mutations of Ras. Antimyeloma effects included induction of tetraploidy followed by apoptosis. Apoptosis correlated with inhibition of aurora activity as shown by reduction of histone 3B phosphorylation. Ectopic expression of aurora A protected MM cells against aurora inhibitors but had no effect on apoptosis induced by bortezomib. As expression of RHAMM in MM contributes to genetic instability, we tested effects of RHAMM. RHAMM overexpression enhanced sensitivity to apoptosis and RHAMM silencing decreased sensitivity. These results suggest potential for aurora kinase inhibitors in MM especially in patients in whom RHAMM is overexpressed.
Publication types
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Clinical Trial
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Aurora Kinases
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Boronic Acids / pharmacology
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Bortezomib
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Cell Line, Transformed
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Drug Screening Assays, Antitumor
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Enzyme Activation / drug effects
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Enzyme Activation / genetics
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Extracellular Matrix Proteins / biosynthesis
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Extracellular Matrix Proteins / genetics
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G2 Phase / drug effects*
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Gene Expression
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Silencing / drug effects
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Hematopoietic Stem Cells / enzymology
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Histones / metabolism
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Humans
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Hyaluronan Receptors / biosynthesis
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Hyaluronan Receptors / genetics
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Interleukin-6 / metabolism
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Lymphocytes / enzymology
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / enzymology
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Multiple Myeloma / genetics
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Mutation
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Phosphorylation / drug effects
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Ploidies
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics
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Proto-Oncogene Proteins p21(ras) / genetics
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Proto-Oncogene Proteins p21(ras) / metabolism
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Pyrazines / pharmacology
Substances
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Antineoplastic Agents
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Boronic Acids
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Extracellular Matrix Proteins
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Histones
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Hyaluronan Receptors
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IL6 protein, human
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Interleukin-6
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Protein Kinase Inhibitors
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Pyrazines
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hyaluronan-mediated motility receptor
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Bortezomib
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Aurora Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins p21(ras)