title: Bortezomib and sphingosine kinase inhibitor interact synergistically to induces apoptosis in BCR/ABl+ cells sensitive and resistant to STI571 through down-regulation Mcl-1.
abstract: Interactions between the proteasome inhibitor, bortezomib, and the sphingosine kinase (SPK1) inhibitor, SKI, were examined in BCR/ABL human leukemia cells. Coexposure of K562 or chronic myeloid leukemia (CML) cells from patients to subtoxic concentrations of SKI (10 μM) and bortezomib (100 nM) resulted in a synergistic increase in caspase-3 cleavage and apoptosis. These events were associated with the downregulation of BCR-ABL and Mcl-1, and a marked reduction in SPK1 expression. In imatinib mesylate-resistant K562 cells that displayed decreased BCR-ABL expression, bortezomib/SKI treatment markedly increased apoptosis and inhibited colony-formation in association with the downregulation of Mcl-1. Finally, the bortezomib/SKI regimen also potently induced the downregulation of BCR/ABL and Mcl-1 in human leukemia cells. Collectively, these findings suggest that combining SKI and bortezomib may represent a novel strategy in leukemia, including apoptosis-resistant BCR-ABL(+) hematologic malignancies.
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, PR China.
authors.forename: Qing-Fang
authors.initials: QF
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.forename: Yue-Feng
authors.initials: YF
authors.lastname: Yang
authors.forename: Feng-Jun
authors.initials: FJ
authors.lastname: Xiao
authors.forename: Chu-Tse
authors.initials: CT
authors.lastname: Wu
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Li-Sheng
authors.initials: LS
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001549:Benzamides; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001897:Boronic Acids; D000069286:Bortezomib; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017853:Phosphotransferases (Alcohol Group Acceptor); D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D011743:Pyrimidines; D000099157:Sphingosine Kinase