Abstract
Medulloblastoma (MB) expresses Src kinase, while aurora kinase A overexpression correlates with poor survival. We thus investigated novel combination treatment with dasatinib and AT9283, inhibitors of Src and aurora kinase, respectively, on MB growth in vitro and in vivo. Treatment with each drug significantly reduced cell viability and combined treatment markedly potentiated this response. AT9283 induced p53 expression, autophagy, and G2/M cell-cycle arrest, while combined treatment induced S phase arrest. Dasatinib treatment caused tumor regression in vivo. Activated Src was detected in 44% MB analyzed. We conclude that further evaluation of this combination therapy for MB is highly warranted.
Keywords:
Aurora kinase; Dasatinib; Medulloblastoma; Survival.
Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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 / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Aurora Kinase A / antagonists & inhibitors*
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Autophagy
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Benzimidazoles / pharmacology*
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Cell Line, Tumor
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Cell Movement
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Cell Proliferation
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Cell Survival
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Dasatinib
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Enzyme Inhibitors / pharmacology*
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G2 Phase
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Humans
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Medulloblastoma / drug therapy*
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Mice
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Mice, Inbred C57BL
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Neoplasm Transplantation
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Protein Kinase Inhibitors / pharmacology
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Pyrimidines / pharmacology*
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Thiazoles / pharmacology*
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Tumor Suppressor Protein p53 / metabolism
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Urea / analogs & derivatives*
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Urea / pharmacology
Substances
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1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea
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Antineoplastic Agents
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Benzimidazoles
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Enzyme Inhibitors
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Protein Kinase Inhibitors
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Pyrimidines
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TP53 protein, human
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Thiazoles
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Tumor Suppressor Protein p53
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Urea
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Aurora Kinase A
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Dasatinib