ArticleClinical cancer research : an official journal of the American Association for Cancer Research2011
HDAC inhibitors potentiate the activity of the BCR/ABL kinase inhibitor KW-2449 in imatinib-sensitive or -resistant BCR/ABL+ leukemia cells in vitro and in vivo.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 76 citations in OpenAlex.
- MK-0457, an Aurora kinase and BCR-ABL inhibitor, is active in patients with BCR-ABL T315I leukemia.Leukemia · 2013Trial
- Molecular Dynamics-Guided Design and Chemoproteomic Profiling of Covalent Kinase Activity Probes.Journal of the American Chemical Society · 2026Article
- Promoting reactive oxygen species accumulation to overcome tyrosine kinase inhibitor resistance in cancer.Cancer cell international · 2024Review
- Chidamide works synergistically with Dasatinib by inducing cell-cycle arrest and apoptosis in acute myeloid leukemia cells.Molecular and cellular biochemistry · 2023Article
- Monitoring Changes in Intracellular Reactive Oxygen Species Levels in Response to Histone Deacetylase Inhibitors.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Dual-Targeted Therapy Circumvents Non-Genetic Drug Resistance to Targeted Therapy.Frontiers in oncology · 2022Review
- Redox Control in Acute Lymphoblastic Leukemia: From Physiology to Pathology and Therapeutic Opportunities.Cells · 2021Review
- Novel HDAC inhibitor MAKV-8 and imatinib synergistically kill chronic myeloid leukemia cells via inhibition of BCR-ABL/MYC-signaling: effect on imatinib resistance and stem cells.Clinical epigenetics · 2020Article
- Review
- Role of HDACs in normal and malignant hematopoiesis.Molecular cancer · 2020Review
- Review
- Overexpression of miR-4433 by suberoylanilide hydroxamic acid suppresses growth of CML cells and induces apoptosis through targeting Bcr-Abl.Journal of Cancer · 2019Article
- Homoharringtonine interacts synergistically with bortezomib in NHL cells through MCL-1 and NOXA-dependent mechanisms.BMC cancer · 2018Article
- Combinatorial effects of histone deacetylase inhibitors (HDACi), vorinostat and entinostat, and adaphostin are characterized by distinct redox alterations.Cancer chemotherapy and pharmacology · 2018Article
- Article
- Multi-kinase inhibitors, AURKs and cancer.Medical oncology (Northwood, London, England) · 2016Review
- Signal transducer and activator of transcription STAT5 is recruited to c-Myc super-enhancer.BMC molecular biology · 2016Article
- Recent advances in the development of Aurora kinases inhibitors in hematological malignancies.Therapeutic advances in hematology · 2015Review
- 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.Oncology letters · 2015Article
- Integrative genomic analysis in K562 chronic myelogenous leukemia cells reveals that proximal NCOR1 binding positively regulates genes that govern erythroid differentiation and Imatinib sensitivity.Nucleic acids research · 2015Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
purposeThe purpose of this study was to determine whether histone deacetylase (HDAC) inhibitors (HDACI) such as vorinostat or entinostat (SNDX-275) could increase the lethality of the dual Bcr/Abl-Aurora kinase inhibitor KW-2449 in various Bcr/Abl(+) human leukemia cells, including those resistant to imatinib mesylate (IM). EXPERIMENTAL
designBcr/Abl(+) chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) cells, including those resistant to IM (T315I, E255K), were exposed to KW-2449 in the presence or absence of vorinostat or SNDX-275, after which apoptosis and effects on signaling pathways were examined. In vivo studies combining HDACIs and KW2449 were carried out by using a systemic IM-resistant ALL xenograft model.
resultsCoadministration of HDACIs synergistically increased KW-2449 lethality in vitro in multiple CML and Ph(+) ALL cell types including human IM resistant cells (e.g., BV-173/E255K and Adult/T315I). Combined treatment resulted in inactivation of Bcr/Abl and downstream targets (e.g., STAT5 and CRKL), as well as increased reactive oxygen species (ROS) generation and DNA damage (γH2A.X). The latter events and cell death were significantly attenuated by free radical scavengers (TBAP). Increased lethality was also observed in primary CD34(+) cells from patients with CML, but not in normal CD34(+) cells. Finally, minimally active vorinostat or SNDX275 doses markedly increased KW2449 antitumor effects and significantly prolonged the survival of murine xenografts bearing IM-resistant ALL cells (BV173/E255K).
conclusionsHDACIs increase KW-2449 lethality in Bcr/Abl(+) cells in association with inhibition of Bcr/Abl, generation of ROS, and induction of DNA damage. This strategy preferentially targets primary Bcr/Abl(+) hematopoietic cells and exhibits enhanced in vivo activity. Combining KW-2449 with HDACIs warrants attention in IM-resistant Bcr/Abl(+) leukemias.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.