title: Methyl-β-cyclodextrin induces programmed cell death in chronic myeloid leukemia cells and, combined with imatinib, produces a synergistic downregulation of ERK/SPK1 signaling.
abstract: Lipid rafts mediate several survival signals in the development of chronic myeloid leukemia (CML). Methyl-β-cyclodextrin (MβCD) is an inhibitor specifically designed to disrupt lipid rafts in cells by depleting the cholesterol component. We hypothesize that treatment of CML cells with MβCD 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 MβCD 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 MβCD and imatinib compared with treatment with either agent alone. MβCD induces programmed cell death in CML cells, and its antileukemia action is synergistic with that of imatinib.
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Qing-Fang
authors.initials: QF
authors.lastname: Li
authors.forename: Li-Sheng
authors.initials: LS
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Feng-Jun
authors.initials: FJ
authors.lastname: Xiao
authors.forename: Yue-Feng
authors.initials: YF
authors.lastname: Yang
authors.forename: Chu-Tse
authors.initials: CT
authors.lastname: Wu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D021962:Membrane Microdomains / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D047392:beta-Cyclodextrins / Q000494:pharmacology*; D000099157:Sphingosine Kinase
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D053148:Caspase 3; D048049:Extracellular Signal-Regulated MAP Kinases; D000068877:Imatinib Mesylate; D017853:Phosphotransferases (Alcohol Group Acceptor); D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D047392:beta-Cyclodextrins; D000099157:Sphingosine Kinase; C108732:methyl-beta-cyclodextrin