title: TKI258, a multi-tyrosine kinase inhibitor is efficacious against human infant/childhood lymphoblastic leukemia in vitro.
abstract: OBJECTIVE
  The goal of the present study was to evaluate if the multiple tyrosine kinase inhibitor (TKI) TKI258 has any treatment value for infant/childhood acute lymphoblatic leukemia (ALL), especially those ALLs bearing the mixed lineage leukemia (MLL) genes.
  
  
  METHODS
  Cell proliferation was measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; cell apoptosis and cell-cycle distribution with flow cytometry. Gene expression at the protein level was determined by western blotting.
  
  
  RESULTS
  These ALL cells were extremely sensitive to TKI258 treatment with a concentration for 50% inhibition of cell proliferation (IC50) values in the nanomolar range in vitro. By combination with mTOR inhibitor RAD001, a synergistic effect on cell death and cell proliferation was observed in these cells.
  
  
  CONCLUSIONS
  TKI258 may become a potent therapeutic agent, either alone or in combination with RAD001, for treatment of ALL, especially the entity with MLL genes.
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: Carsten-Oliver
authors.initials: CO
authors.lastname: Schulz
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*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004357:Drug Synergism; D000068338:Everolimus; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D020128:Inhibitory Concentration 50; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015363:Quinolones / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014178:Translocation, Genetic
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; C497422:KMT2A protein, human; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D051788:Myeloid-Lymphoid Leukemia Protein; D000068338:Everolimus; D011495:Histone-Lysine N-Methyltransferase; D011505:Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: IC50 (concentration for 50% inhibition of cell proliferation); Infant and childhood ALL; cell apoptosis; cell proliferation; mTOR inhibitor RAD001; multi-tyrosine kinase inhibitor TKI258