Abstract
Although c-Kit is expressed on the surface of myeloma cells in one-third of myeloma patients, the efficacy of imatinib mesylate for patients with myeloma is still controversial. To investigate the combinatorial effect of OSU-03012 and imatinib mesylate, we treated a c-Kit-expressing myeloma cell line, TIB-196, with DMSO, OSU-03012 alone, imatinib mesylate alone and OSU-03012 plus imatinib mesylate. OSU-03012 sensitized TIB-196 cells to imatinib mesylate cytotoxicity. p-STAT3 (Tyr705), as well as down-stream cyclin D1 and Mcl-1, was down regulated. Additionally, there was markedly increased p-AMPK (Thr172) and down-regulation of p-p70S6K (Thr386) in the combination group. Combined treatments targeting c-Kit, AMPK and STAT3 may be a potential strategy for treating patients with myeloma.
Copyright 2009 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / metabolism
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AMP-Activated Protein Kinases / physiology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Benzamides
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical
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Drug Resistance, Neoplasm / drug effects*
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Drug Synergism
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HL-60 Cells
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Humans
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Imatinib Mesylate
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology
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Piperazines / administration & dosage*
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Protein Kinase Inhibitors / pharmacology
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Pyrazoles / administration & dosage
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Pyrazoles / pharmacology*
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Pyrimidines / administration & dosage*
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STAT3 Transcription Factor / metabolism
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STAT3 Transcription Factor / physiology*
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Signal Transduction / drug effects
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Sulfonamides / administration & dosage
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Sulfonamides / pharmacology*
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Time Factors
Substances
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Benzamides
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OSU 03012
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Piperazines
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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STAT3 Transcription Factor
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STAT3 protein, human
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Sulfonamides
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Imatinib Mesylate
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AMP-Activated Protein Kinases