Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice

Abstract

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 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 demonstrated 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% B220+leukemia cells were found in peripheral blood, compared with 34% B220+leukemia cells in the placebo group. Treatment with omacetaxine decreased the number of leukemia stem cells and prolonged survival of mice with BCR-ABL induced CML or B-ALL.

Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis

“…These observations indicate that tetrandrine citrate is a novel orally active tetrandrine salt that can eradicate IM-resistant Ph + CML cells in vitro and in vivo by depleting Bcr-Abl and β-catenin proteins and disrupting the Bcr-Abl/β-catenin axis. At least two advantages of this strategy are noted: (1) depletion of Bcr-Abl protein may offer the potential to override resistance to TKIs caused by Bcr-Abl kinase mutations, which is supported by a recent study (Chen et al, 2009b); (2) depletion of Bcr-Abl and β-catenin proteins results in the disruption of the Bcr-Abl/ β-catenin axis that is essential for LSC survival and self-renewal, and thus provides a better therapeutic approach to CML. Indeed, our results indicate that this compound can effectively ablate the primitive LSCs (CD34 + leukemia cells), which are exceptionally refractory to be killed by the TKIs or conventional chemotherapeutic agents (Holyoake et al, 1999;Elrick et al, 2005;Holtz et al, 2005;Barnes and Melo, 2006).…”

Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors

“…Franck E. Nicolini, 1 H. Jean Khoury, 2 Luke Akard, 3 Delphine Rea, 4 Hagop Kantarjian, 5 Michele Baccarani, 6 Janis Leonoudakis, 7 Adam Craig, 8 Annie-Claude Benichou, 8 …”

Molecular and cellular bases of chronic myeloid leukemia

“…The cyclopamine, a Hedgehog inhibitor, reduces CML stem cell population and extend survive of CML mice (Zhao et al, 2009). Omacetaxine, a Mcl-1 inhibitor, is also shown to inhibit LSCs effectively (Chen et al, 2009a). Another strategy is to identify key functional pathways specific for LSCs but not normal HSCs, and target these pathways in treating CML without causing significant harm to normal HSCs (Fig.…”