Abstract
Bcr-Abl tyrosine kinase inhibitors (TKIs) have been a remarkable success for the treatment of Ph(+) chronic myeloid leukemia (CML). However, a significant proportion of patients treated with TKIs develop resistance because of leukemia stem cells (LSCs) and T315I mutant Bcr-Abl. Here we describe the unknown activity of the natural product berbamine that efficiently eradicates LSCs and T315I mutant Bcr-Abl clones. Unexpectedly, we identify CaMKII γ as a specific and critical target of berbamine for its antileukemia activity. Berbamine specifically binds to the ATP-binding pocket of CaMKII γ, inhibits its phosphorylation and triggers apoptosis of leukemia cells. More importantly, CaMKII γ is highly activated in LSCs but not in normal hematopoietic stem cells and coactivates LSC-related β-catenin and Stat3 signaling networks. The identification of CaMKII γ as a specific target of berbamine and as a critical molecular switch regulating multiple LSC-related signaling pathways can explain the unique antileukemia activity of berbamine. These findings also suggest that berbamine may be the first ATP-competitive inhibitor of CaMKII γ, and potentially, can serve as a new type of molecular targeted agent through inhibition of the CaMKII γ activity for treatment of leukemia.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / chemistry
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Adenosine Triphosphate / metabolism
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Animals
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Apoptosis / drug effects
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Benzamides
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Benzylisoquinolines / chemistry
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Benzylisoquinolines / metabolism
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Benzylisoquinolines / pharmacology*
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Blotting, Western
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Calcium-Calmodulin-Dependent Protein Kinase Type 1 / chemistry
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Calcium-Calmodulin-Dependent Protein Kinase Type 1 / genetics
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Calcium-Calmodulin-Dependent Protein Kinase Type 1 / metabolism*
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Fusion Proteins, bcr-abl / antagonists & inhibitors
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / metabolism
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HEK293 Cells
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Humans
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Imatinib Mesylate
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K562 Cells
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Models, Molecular
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Mutation
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Piperazines / pharmacology
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Protein Binding
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Protein Kinase Inhibitors / pharmacology
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Pyrimidines / pharmacology
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Benzamides
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Benzylisoquinolines
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Imatinib Mesylate
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Adenosine Triphosphate
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Protein-Tyrosine Kinases
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Fusion Proteins, bcr-abl
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CAMK1G protein, human
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Calcium-Calmodulin-Dependent Protein Kinase Type 1
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berbamine