Abstract
Heat shock protein 90 (Hsp90) contains amino (N)-terminal domain, carboxyl(C)-terminal domain, and middle domains, which activate Hsp90 chaperone function cooperatively in tumor cells. One terminal occupancy might influence another terminal binding with inhibitor. The Bcr-Abl kinase is one of the Hsp90 clients implicated in the pathogenesis of chronic myeloid leukemia (CML). Present studies demonstrate that double inhibition of the N- and C-terminal termini can disrupt Hsp90 chaperone function synergistically, but not antagonistically, in Bcr-Abl-positive human leukemia cells. Furthermore, both the N-terminal inhibitor 17-AAG and the C-terminal inhibitor cisplatin (CP) have the capacity to suppress progenitor cells; however, only CP is able to inhibit leukemia stem cells (LSCs) significantly, which implies that the combinational treatment is able to suppress human leukemia in different mature states.
Keywords:
Bcr-Abl; Hsp90; amino terminal; carboxyl terminal; imatinib-resistant.
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Apoptosis / drug effects*
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Benzoquinones / pharmacology*
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Cell Proliferation / drug effects*
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Cisplatin / pharmacology*
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Dose-Response Relationship, Drug
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Drug Synergism
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Fusion Proteins, bcr-abl / genetics*
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Gene Fusion*
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / chemistry
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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K562 Cells
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Lactams, Macrocyclic / pharmacology*
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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 / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Protein Domains
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Signal Transduction / drug effects
Substances
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BCR-ABL1 fusion protein, human
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Benzoquinones
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HSP90 Heat-Shock Proteins
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Lactams, Macrocyclic
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tanespimycin
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Fusion Proteins, bcr-abl
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Cisplatin