Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond

Melo, Junia V.; Chuah, Charles

doi:10.1182/asheducation-2008.1.427

Cited by 49 publications

(36 citation statements)

References 73 publications

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“…2,3 However, molecular studies of imatinib-treated patients in remission demonstrated that Bcr-Abl expression is still detectable in most cases, and discontinuation of imatinib therapy often results in disease relapse. 4,5 Limited duration of imatinib response is also common in advanced CML patients, and imatinib resistance can occur at any stage of the disease. 5,6 Acquired imatinib resistance and disease progression are frequently characterized by Bcr-Abl mutations and posttranslational modifications that affect imatinib binding and kinase inhibition.…”

mentioning

confidence: 99%

Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis

Sun

Kapuria

Peterson

et al. 2011

Blood

109

101

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IntroductionChronic myelogenous leukemia (CML) is associated with a chromosomal abnormality in the hematopoietic stem cell that results in the expression of Bcr-Abl with unregulated tyrosine kinase activity. 1 These observations supported the development and clinical testing of the first Bcr-Abl kinase inhibitor, imatinib, which demonstrated remarkable clinical efficacy in CML patients. Imatinib is the frontline therapy for CML and other Bcr-Ablexpressing leukemias, and most patients treated with imatinib in the chronic phase achieve a complete cytogenetic response. 2,3 However, molecular studies of imatinib-treated patients in remission demonstrated that Bcr-Abl expression is still detectable in most cases, and discontinuation of imatinib therapy often results in disease relapse. 4,5 Limited duration of imatinib response is also common in advanced CML patients, and imatinib resistance can occur at any stage of the disease. 5,6 Acquired imatinib resistance and disease progression are frequently characterized by Bcr-Abl mutations and posttranslational modifications that affect imatinib binding and kinase inhibition. 5,6 Some of the molecular changes in imatinib-resistant disease can be overcome with second-generation tyrosine kinase inhibitors, which bind Bcr-Abl with higher affinity or inhibit imatinib-insensitive kinases associated with resistance. [7][8][9][10][11] However, the activity of these inhibitors can also be limited by mutations and other mechanisms. [12][13][14] These observations suggest that additional approaches and targeting strategies may be needed to provide long-term effective treatment for CML patients.Kinase inhibition by small molecules that bind the ATP or the switch pocket region of Bcr-Abl are effective inhibitors but require continuous treatment because Bcr-Abl protein levels themselves are not directly regulated through kinase inhibition. Some evidence suggests that Bcr-Abl can function as a protein scaffold to organize signaling complexes that are not fully dependent on kinase activity. 15,16 These observations suggest that compounds that modulate Bcr-Abl protein levels may be more effective and appropriate for CML therapy in some settings. In light of that possibility and as a novel approach to overcoming kinase inhibitor resistance, several compounds have been described that affect Bcr-Abl function through mechanisms other than direct kinase inhibition. These include heat shock protein 90 (Hsp90) inhibitors, arsenic trioxide, homoharringtonine, histone deacetylase inhibitors, proteasome inhibitors, PP2A activators, and others. 5,10 All are reported to lead to CML cell death through down-regulation of Bcr-Abl expression or a loss of Bcr-Abl stability. However, most of these compounds reduce Bcr-Abl levels only after extended incubation intervals and display only limited selectivity for Bcr-Abl, which may increase their toxicity and decrease their clinical utility. [17][18][19] Additional compounds that induce rapid changes in Bcr-Abl levels with limited impact on other proteins are ...

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mentioning

confidence: 99%

Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis

Sun

Kapuria

Peterson

et al. 2011

Blood

109

101

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“…While the introduction of the Bcr-Abl kinase inhibitor, imatinib, into the clinical armamentarium, represents an important advance in the treatment of CML, the development of drug resistance constitutes a significant barrier to curing this disease (2,17). The present study demonstrated that treatment with the HDACi, SAHA (0.5-8 µM), induced cell death in imatinib-sensitive K562 cells, as well as imatinib-resistant K562G cells, in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 59%

“…The current recommended first line therapy for patients with newly diagnosed CML, is imatinib. However, resistance to imatinib is a significant problem, despite the good clinical results achieved with this tyrosine kinase inhibitor in the treatment of CML (2). Therefore, the identification of novel therapeutic agents, in addition to an understanding of their underlying mechanisms, is necessary in order to improve the outcome in patients with CML.…”

Section: Introductionmentioning

confidence: 99%

Proteasome inhibitor MG-132 enhances histone deacetylase inhibitor SAHA-induced cell death of chronic myeloid leukemia cells by an ROS-mediated mechanism and downregulation of the Bcr-Abl fusion protein

Zhu

Xiao

et al. 2015

Oncology Letters

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Abstract.Recently, there has been progress in the treatment of chronic myeloid leukemia (CML). However, novel therapeutic strategies are required in order to address the emerging problem of imatinib resistance. Histone deacetylase inhibitors (HDACi) and proteasome inhibitors are promising alternatives, and may be amenable to integration with current therapeutic approaches. However, the mechanisms underlying the interaction between these two agents remain unclear. The present study assessed the cytotoxic effect of the HDACi, suberoylanilide hydroxamic acid (SAHA), in combination with the proteasome inhibitor, MG-132, in imatinib-sensitive K562 and imatinib-resistant K562G cells, and investigated the mechanism underlying this effect. Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method and protein expression levels were determined by western blotting. Reactive oxygen species (ROS) generation levels were observed under a fluorescence microscope The results indicated that SAHA and MG-132 act in a synergistic manner to induce cell death in K562 and K562G cells. This effect was associated with Bcr-Abl downregulation and the production of ROS. Notably, the ROS scavenger, N-acetyl-L-cysteine, almost fully reversed the cell death and Bcr-Abl downregulation that was induced by the combination of SAHA and MG-132. By contrast, the pan-caspase inhibitor, z-VAD-fmk, only partially reversed the cell death induced by these two drugs in CML cells. These results indicated that increased intracellular ROS levels are important in the induction of cell death and the downregulation of Bcr-Abl. In conclusion, the present results suggested that combined SAHA and MG-132 may be a promising treatment for CML.

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“…Despite its therapeutic efficacy, the development of imatinib-resistance and intolerance is still a challenging problem for most patients (7). Many novel compounds and therapeutic approaches are currently being investigated preclinically and clinically to overcome imatinib resistance (8). Dasatinib and nilotinib are the second generation TKIs that are more effective and safer in patients with imatinib-resistance and intolerance (8).…”

Section: Introductionmentioning

confidence: 99%

“…Many novel compounds and therapeutic approaches are currently being investigated preclinically and clinically to overcome imatinib resistance (8). Dasatinib and nilotinib are the second generation TKIs that are more effective and safer in patients with imatinib-resistance and intolerance (8). However, the development of novel Bcr-Abl mutants resistant to these new small-molecule inhibitors and adverse effects of these agents are still significant problems (9).Therefore, alternative therapeutic approaches are required and natural products have been investigated because of their potential in cancer prevention and treatment.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of Apigenin, a Plant Flavonoid, for Imatinib-Sensitive and Resistant Chronic Myeloid Leukemia Cells

Solmaz

Gökbulut

Cincin

et al. 2014

Nutrition and Cancer

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Despite the presence of many therapeutic regimens like imatinib and other tyrosine kinase inhibitors, the development of resistance, intolerance, and side effects makes chronic myeloid leukemia (CML) therapy challenging. Thus, there is a need to discover novel drugs for CML patients. In this study, we attempted to assess apigenin, a common plant dietary flavonoid, in terms of its cytotoxic, apoptotic, and cytostatic effects on imatinib-sensitive and resistant Philadelphia-positive CML cells. We analyzed apigenin's effects on cell proliferation, apoptosis, caspase-3 activity, loss of mitochondrial membrane potential, and cell cycle progression in K562 and K562/IMA3 cells. Furthermore, we described genes and Results of our study revealed that apigenin has cytotoxic and apoptotic effects on both cell types. We also displayed that apigenin induced G2/M arrest in K562 cells while arresting K562/IMA3 cells in S phase especially at the highest apigenin concentration. The expression analysis identified a set of genes that were regulated by apigenin in K652 and K562/IMA3 cells. Association of modulated genes with biological functional groups identified several networks affected by apigenin including cell survival, proliferation, cell death, cell cycle, and cell signalling pathways.

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Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond

Cited by 49 publications

References 73 publications

Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis

Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis

Proteasome inhibitor MG-132 enhances histone deacetylase inhibitor SAHA-induced cell death of chronic myeloid leukemia cells by an ROS-mediated mechanism and downregulation of the Bcr-Abl fusion protein

Therapeutic Potential of Apigenin, a Plant Flavonoid, for Imatinib-Sensitive and Resistant Chronic Myeloid Leukemia Cells

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