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Blood, 15 May 2008, Vol. 111, No. 10, pp. 5086-5092. Prepublished online as a Blood First Edition Paper on February 28, 2008; DOI 10.1182/blood-2007-06-098079. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-06-098079v1 111/10/5086    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Nishioka, C. Articles by Yokoyama, A. PubMed PubMed Citation Articles by Nishioka, C. Articles by Yokoyama, A. Related Collections Signal Transduction Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Ki11502, a novel multitargeted receptor tyrosine kinase inhibitor, induces growth arrest and apoptosis of human leukemia cells in vitro and in vivo Chie Nishioka1,2, Takayuki Ikezoe1, Jing Yang1, Atsushi Miwa3, Taizo Tasaka4, Yoshio Kuwayama1, Kazuto Togitani1, H. Phillip Koeffler5, and Akihito Yokoyama1 1 Department of Hematology and Respiratory Medicine, Kochi University, Kochi, Japan; 2 Japanese Society for the Promotion of Science, Tokyo, Japan; 3 Discovery Research Laboratories, Kirin Pharma, Gunma, Japan; 4 Division of Hematology, Department of Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan; and 5 Department of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA Ki11502 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor with selectivity against platelet-derived growth factor receptor alpha/beta (PDGFR/β). Ki11502 (0.1-1 nM, 2 days) profoundly caused growth arrest, G0/G1 cell-cycle arrest, and apoptosis associated with down-regulation of Bcl-2 family proteins in the eosinophilic leukemia EOL-1 cells having the activated FIP1-like 1/PDGFR fusion gene. Ki11502 decreased levels of p-PDGFR and its downstream signals, including p-Akt, p-ERK, and p-STAT5, in EOL-1 cells. Of note, Ki11502 was also active against imatinib-resistant PDGFRT674I mutant. In addition, Ki11502 inhibited proliferation of biphenotipic leukemia MV4-11 and acute myelogenous leukemia MOLM13 and freshly isolated leukemia cells having activating mutations in FMS-like tyrosine kinase 3 (FLT3). This occurred in parallel with the drug inhibiting FLT3 and its downstream signal pathways, as measured by fluorescence-activated cell sorting using the phospho-specific antibodies. In addition, Ki11502 totally inhibited proliferation of EOL-1 cells growing as tumor xenografts in SCID mice without any noticeable adverse effects. Taken together, Ki11502 has profound antiproliferative effects on select subsets of leukemia including those possessing imatinib-resistant mutation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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