Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice
Department of Medicine, Division of Hematology/Oncology
Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Fusion Proteins, bcr-abl; Gene Expression Regulation, Leukemic; HSP90 Heat-Shock Proteins; Harringtonines; Humans; K562 Cells; Leukemia, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplastic Stem Cells; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Radiation Chimera; Recombinant Fusion Proteins; Transduction, Genetic
Life Sciences | Medicine and Health Sciences
Omacetaxine mepesuccinate (formerly homoharringtonine) is a molecule with a mechanism of action that is different from tyrosine kinase inhibitors, and its activity in chronic myeloid leukemia (CML) seems to be independent of the BCR-ABL mutation status. Using BCR-ABL-expressing myelogenous and lymphoid cell lines and mouse models of CML and B-cell acute lymphoblastic leukemia (B-ALL) induced by wild-type BCR-ABL or T315I mutant-BCR-ABL, we evaluated the inhibitory effects of omacetaxine on CML and B-ALL. We showed that more than 90% of the leukemic stem cells were killed after treatment with omacetaxine in vitro. In contrast, less than 9 or 25% of the leukemic stem cells were killed after treating with imatinib or dasatinib, respectively. After 4 days of treatment of CML mice with omacetaxine, Gr-1(+)myeloid leukemia cells decreased in the peripheral blood of the treated CML mice. In the omacetaxine-treated B-ALL mice, only 0.8% of the B220(+)leukemia cells were found in peripheral blood, compared with 34% of the B220(+)leukemia cells in the placebo group. Treatment with omacetaxine decreased the number of leukemia stem cells and prolonged the survival of mice with BCR-ABL-induced CML or B-ALL.
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Citation: Leukemia. 2009 Aug;23(8):1446-54. Epub 2009 Mar 26. Link to article on publisher's site