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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.

AbstractBACKGROUND/AIM:
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.
MATERIALS AND 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.
CONCLUSION:
TKI258 may become a potent therapeutic agent, either alone or in combination with RAD001, for treatment of BCR-ABL(+) leukemia.
AuthorsJan Eucker, Chuanbing Zang, Yongan Zhou, Xinhua Li, Piet Habbel, Christian Neumann, Christian Scholz, Hongyu Liu
JournalAnticancer research (Anticancer Res) Vol. 34 Issue 9 Pg. 4909-14 (Sep 2014) ISSN: 1791-7530 [Electronic] Greece
PMID25202073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
Chemical References
  • 4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
  • Antineoplastic Agents
  • Benzimidazoles
  • Protein Kinase Inhibitors
  • Quinolones
  • Everolimus
  • Fusion Proteins, bcr-abl
  • TOR Serine-Threonine Kinases
  • Sirolimus
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Benzimidazoles (pharmacology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Drug Synergism
  • Everolimus
  • Fusion Proteins, bcr-abl (genetics)
  • Humans
  • Leukemia (drug therapy, genetics)
  • Protein Kinase Inhibitors (pharmacology)
  • Quinolones (pharmacology)
  • Sirolimus (analogs & derivatives, pharmacology)
  • TOR Serine-Threonine Kinases (antagonists & inhibitors)

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