Journal
ANTI-CANCER DRUGS
Volume 23, Issue 1, Pages 22-31Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CAD.0b013e32834a099c
Keywords
chronic myeloid leukemia; extracellular signal-regulated kinase; imatinib; methyl-beta-cyclodextrin; sphingosine kinase 1
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Funding
- Chinese National Natural Science Foundation [30900634]
- National Mega-project of Science Research of China [2009ZX09503-019, 2009ZX09503-002]
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Lipid rafts mediate several survival signals in the development of chronic myeloid leukemia (CML). Methyl-beta-cyclodextrin (M beta CD) is an inhibitor specifically designed to disrupt lipid rafts in cells by depleting the cholesterol component. We hypothesize that treatment of CML cells with M beta CD and imatinib could reduce imatinib resistance. Apoptotic and autophagic cell death was assayed using annexin V-propidium iodide double staining, immunoblotting, and immunocytochemistry. We next investigated whether M beta CD could enhance the cytotoxicity of imatinib in imatinib-sensitive and imatinib-resistant K562 cells. Extracellular signal-regulated kinase/sphingosine kinase 1 signaling downstream of lipid raft-activated signaling pathways was significantly inhibited by treatment of cells with a combination of M beta CD and imatinib compared with treatment with either agent alone. M beta CD induces programmed cell death in CML cells, and its antileukemia action is synergistic with that of imatinib. Anti-Cancer Drugs 23: 22-31 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
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