Abstract
Effects of the tyrphostin adaphostin and bortezomib were examined in Bcr/Abl+ leukemia cell resistant to imatinib mesylate secondary to Bcr/Abl point mutations. Adaphostin was equally effective in inducing mitochondrial damage, caspase activation, JNK activation, and Raf-1, phospho-Stat3 and -Stat5 inactivation in mutant and wild-type cells, but differentially down-regulated phospho-Bcr/Abl. Adaphostin and bortezomib synergistically induced apoptosis in wild-type and mutant cells, including T315I mutants. Notably, adaphostin+/-bortezomib potently induced ROS and lethality in mutant cells, effects attenuated by the antioxidant NAC. These findings indicate that adaphostin+/-bortezomib circumvent imatinib resistance due to Bcr/Abl point mutations most likely through ROS generation.
Publication types
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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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Adamantane / analogs & derivatives*
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Adamantane / pharmacology
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Benzamides
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Boronic Acids / pharmacology*
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Bortezomib
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Cell Line, Tumor
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Fusion Proteins, bcr-abl / drug effects
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Fusion Proteins, bcr-abl / genetics*
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Hematopoietic Stem Cells / drug effects*
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Hematopoietic Stem Cells / pathology
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Hematopoietic Stem Cells / physiology
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Humans
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Hydroquinones / pharmacology*
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Imatinib Mesylate
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Kinetics
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Mutation*
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Oxidative Stress / drug effects*
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Piperazines / pharmacology*
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Point Mutation
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Pyrazines / pharmacology*
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Pyrimidines / pharmacology*
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Reactive Oxygen Species / metabolism
Substances
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Antineoplastic Agents
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Benzamides
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Boronic Acids
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Hydroquinones
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NSC 680410
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Piperazines
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Pyrazines
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Pyrimidines
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Reactive Oxygen Species
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Bortezomib
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Imatinib Mesylate
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Fusion Proteins, bcr-abl
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Adamantane