Abstract
Multidrug resistance (MDR) due to over-expression of the MDR1 (ABCB1) gene and its P-glycoprotein (Pgp) product is an obstacle in the treatment of hematological malignancies. In this study, we have evaluated the potency of KT-5720 to reverse Pgp-dependent MDR in vitro and in vivo. KT-5720 (but not its close derivatives, K252a and K252b) reversed multidrug resistance of LM1/MDR cell line at non-toxic concentrations and increased accumulation of rhodamine 123 (Rh123). KT-5720 significantly reversed MDR1-dependent resistance of primary malignant cells from patients with chronic myelogenous leukemia in blast crisis (CML-BC) and advanced multiple myeloma (MM). Moreover, KT-5720 (at 5 mg/kg) sensitized the bone marrow of MDR1 transgenic mice model towards daunorubicin (at 8 mg/kg) without general toxic effects. Therefore, KT-5720 can be considered as candidate for combination therapy in various hematological malignancies where Pgp activity is a major impediment for cure.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Blast Crisis / drug therapy*
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Blast Crisis / pathology
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Carbazoles / pharmacology*
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Carbazoles / therapeutic use
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Cell Line, Tumor
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Daunorubicin / pharmacology
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Drug Resistance, Neoplasm / drug effects*
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Humans
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Indoles / pharmacology*
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Indoles / therapeutic use
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / pathology
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Pyrroles / pharmacology*
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Pyrroles / therapeutic use
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antibiotics, Antineoplastic
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Carbazoles
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Enzyme Inhibitors
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Indoles
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Pyrroles
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KT 5720
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Daunorubicin