Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia. Leuk Lymphoma

The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Leukemia & lymphoma (Impact Factor: 2.89). 02/2008; 49(1):19-26. DOI: 10.1080/10428190701713689
Source: PubMed

ABSTRACT The BCR-ABL kinase inhibitor imatinib has shown significant efficacy in chronic myeloid leukemia (CML) and is the standard front-line therapy for patients in chronic phase. However, a substantial number of patients are either primarily refractory or acquire resistance to imatinib. While a number of mechanisms are known to confer resistance to imatinib, increasing evidence has demonstrated a role for BCR-ABL-independent pathways. The Src-family kinases (SFKs) are one such pathway and have been implicated in imatinib resistance. Additionally, these kinases are key to the progression of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The dual SFK/BCR-ABL inhibitor dasatinib is now clinically available and has markedly greater potency compared with imatinib against native BCR-ABL and the majority of imatinib-resistant BCR-ABL mutants. Therefore, this agent, as well as other dual SFK/BCR-ABL inhibitors under development, could provide added therapeutic advantages by overcoming both BCR-ABL-dependent (i.e. BCR-ABL mutations) and -independent forms of imatinib resistance and delaying transition to advanced phase disease. In this review, we discuss the preclinical and clinical evidence demonstrating the involvement of SFKs in imatinib resistance and the progression of CML and Ph+ ALL, as well as the potential role of dual SFK/BCR-ABL inhibition in the management of these diseases.

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    • "e l s e v i e r . c o m / l o c a t e / b i o c h e m p h a r m cells [16]. In light of these data, much attention has been focused on the development of anti-cancer drugs that target oncogenic Src kinase [17] [18]. "
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    ABSTRACT: Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity.
    Biochemical pharmacology 01/2013; DOI:10.1016/j.bcp.2013.01.012 · 4.65 Impact Factor
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    • "Inhibition of Lyn with SFK inhibitors reduced prosurvival signaling and reversed imatinib resistance in CML cells (Ito et al., 2007; Nam et al., 2007). Moreover, the dual-specificity BCR-Abl/SFK inhibitors (i.e., dasatinib, sorafenib, nilotinib) effectively treat patients who are nonresponsive to imatinib therapy (Li, 2008; Wu et al., 2008). "
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    ABSTRACT: Imatinib, a BCR-Abl inhibitor, is a successful front-line treatment for chronic myelogenous leukemia (CML). Despite the success of imatinib, multiple mechanisms of resistance remain a problem, including overexpression of Lyn kinase (Lyn) and Bcl-2 family antiapoptotic proteins. Profiling micro-RNA (miRNA) expression in a model of Lyn-mediated imatinib-resistant CML (MYL-R) identified approximately 30 miRNAs whose expression differed >2-fold compared with drug-sensitive MYL cells. In particular, the expression of the miR181 family (a-d) was significantly reduced (∼11- to 25-fold) in MYL-R cells. Incubation of MYL-R cells with a Lyn inhibitor (dasatinib) or nucleofection with Lyn-targeting short interfering RNA increased miR181b and miR181d expression. A similar Lyn-dependent regulation of miR181b and miR181d was observed in imatinib-resistant K562 CML cells. Sequence analysis of potential targets for miR181 regulation predicted myeloid cell leukemia-1 (Mcl-1), a Bcl-2 family member whose expression is increased in MYL-R cells and drug-resistant leukemias. Inhibition of Lyn or rescue of miR181b expression reduced Mcl-1 expression in the MYL-R cells. To further investigate the mechanism of Mcl-1 repression by miR181, a luciferase reporter construct incorporating the Mcl-1 3'-untranslated region was tested. Overexpression of miR181b reduced luciferase activity, whereas these effects were ablated by the mutation of the seed region of the miR181 target site. Finally, stimulation of Lyn expression by 1,25-dihydroxyvitamin D(3) treatment in HL-60 cells, a cell model of acute myelogenous leukemia, decreased miR181b expression and increased Mcl-1 expression. In summary, our results suggest that Lyn-dependent regulation of miR181 is a novel mechanism of regulating Mcl-1 expression and cell survival.
    Molecular pharmacology 11/2010; 78(5):811-7. DOI:10.1124/mol.110.066258 · 4.12 Impact Factor
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    • "initially effective, although many patients relapse over time [43]. Tumor re-growth and disease relapse may be due to the development of therapeutic resistance, insufficient primary therapy, or to a population of intrinsically resistant cancer cells. "
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    ABSTRACT: Cancer is responsible for one in eight deaths worldwide, with more than twelve million new cases diagnosed yearly. A large percentage of patients die after developing cancer despite aggressive treatment, indicating a need for new approaches to cancer therapy. The push for development of novel diagnostic and therapeutic agents has allowed translational cancer research to flourish. Genomic and proteomic technologies have generated an enormous amount of information critical to expanding our understanding of cancer biology. New research on the differences between normal and malignant cell biology has paved the way for the development of drugs targeted to specific biological molecules, potentially increasing antitumor efficacy while minimizing the toxicity to the patient that is seen with conventional therapeutics. Current targets in include regulators of cell cycle, angiogenesis, apoptosis, DNA repair, and growth factors and their receptors. Collaboration among researchers, clinicians, and pharmaceutical companies is vital to conducting clinical trials to translate laboratory findings into clinically applicable therapeutics. In this review, we discuss current therapeutic approaches and present an introduction to a wide range of topics undergoing investigation in an effort to highlight the importance of translational research in the development of clinically relevant therapeutic strategies.
    American Journal of Translational Research 01/2010; 2(1):1-18. · 3.23 Impact Factor
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