title: The multi-tyrosine kinase inhibitor TKI258, alone or in combination with RAD001, is effective for treatment of human leukemia with BCR-ABL translocation in vitro.
abstract: OBJECTIVE
  BCR-ABL-positive (BCR-ABL(+)) leukemia is very difficult to treat although much improvement has been achieved due to the clinical application of imatinib and the second-generation tyrosine kinase inhibitors (TKIs). This study aimed to evaluate for the first time the treatment value of the multiple tyrosine kinase inhibitor TKI258 in BCR-ABL(+) leukemia.
  
  
  METHODS
  Proliferation of different BCR-ABL(+) leukemic cells was measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; cell apoptosis with Annexin V/propidium iodide (PI) and flow cytometry. Gene expression at the protein level was determined by western blotting.
  
  
  RESULTS
  This drug showed treatment efficacy in naïve and imatinib-resistant BCR-ABL(+) leukemia cells, particularly in cells harboring T315I-mutated BCR-ABL, for which no effective inhibitor is available to date. By combination with the mTOR inhibitor RAD001, a synergistic effect on cell proliferation was observed in these cell lines.
  
  
  CONCLUSIONS
  TKI258 may become a potent therapeutic agent, either alone or in combination with RAD001, for treatment of BCR-ABL(+) leukemia.
authors.affiliation: Department of Hematology and Oncology, Charité-University Medicine, Berlin, Germany jan.eucker@charite.de hongyu.liu@charite.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Eucker
authors.affiliation: Department of Hematology and Oncology, Charité-University Medicine, Berlin, Germany.
authors.forename: Chuanbing
authors.initials: C
authors.lastname: Zang
authors.affiliation: Central Research Laboratory, Taiyuan Central Hospital, Taiyuan, P.R. China.
authors.forename: Yongan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Central Research Laboratory, Taiyuan Central Hospital, Taiyuan, P.R. China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hematology and Oncology, Charité-University Medicine, Berlin, Germany.
authors.forename: Piet
authors.initials: P
authors.lastname: Habbel
authors.affiliation: Department of Hematology and Oncology, Charité-University Medicine, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Neumann
authors.affiliation: Department of Hematology and Oncology, Charité-University Medicine, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Scholz
authors.affiliation: Department of Hematology and Oncology, Charité-University Medicine, Berlin, Germany jan.eucker@charite.de hongyu.liu@charite.de.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D000068338:Everolimus; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D000068338:Everolimus; D016044:Fusion Proteins, bcr-abl; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: BCR-ABL+ leukemia; cell apoptosis; cell proliferation; mTOR inhibitor RAD001; multi-tyrosine kinase inhibitor TKI258