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.

作者：Jan Eucker, Chuanbing Zang, Yongan Zhou, Xinhua Li, Piet Habbel, Christian Neumann, Christian Schölz, Hongyu Liu · 发表于：PubMed · 年份：2014 · 被引用次数：7 · 研究领域：Chronic Myeloid Leukemia Treatments、Eosinophilic Disorders and Syndromes、Protein Degradation and Inhibitors

BACKGROUND/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.