The HDAC inhibitor SB939 overcomes resistance to BCR-ABL kinase Inhibitors conferred by the BIM deletion polymorphism in chronic myeloid leukemia
| Autor: | S. Tiong Ong, Muhammad Rauzan, Charles Chuah, Tun Kiat Ko |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pracinostat Fusion Proteins bcr-abl lcsh:Medicine Apoptosis Biochemistry Lung and Intrathoracic Tumors Hematologic Cancers and Related Disorders chemistry.chemical_compound Spectrum Analysis Techniques 0302 clinical medicine hemic and lymphatic diseases Medicine and Health Sciences Medicine Enzyme Inhibitors Post-Translational Modification Phosphorylation lcsh:Science Genetics Multidisciplinary Bcl-2-Like Protein 11 Cell Death Pharmaceutics Myeloid leukemia hemic and immune systems Hematology Flow Cytometry Myeloid Leukemia STAT proteins Leukemia Oncology Cell Processes Spectrophotometry 030220 oncology & carcinogenesis Cytophotometry biological phenomena cell phenomena and immunity Tyrosine kinase Research Article RNA Splicing Immunoblotting Chronic Myeloid Leukemia Molecular Probe Techniques Antineoplastic Agents Research and Analysis Methods 03 medical and health sciences Drug Therapy Leukemia Myelogenous Chronic BCR-ABL Positive Leukemias Humans Progenitor cell Molecular Biology Techniques Molecular Biology neoplasms Myeloproliferative Disorders business.industry lcsh:R Biology and Life Sciences Cancers and Neoplasms Proteins Cell Biology medicine.disease Non-Small Cell Lung Cancer respiratory tract diseases Histone Deacetylase Inhibitors 030104 developmental biology Imatinib mesylate chemistry Cell culture Cancer research Benzimidazoles lcsh:Q K562 Cells business Gene Deletion K562 cells |
| Zdroj: | PLoS ONE, Vol 12, Iss 3, p e0174107 (2017) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the BCL2-like 11 (BIM) gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat) is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance. We found that SB939 corrects BIM pre-mRNA splicing in CML cells with the BIM deletion polymorphism, and induces apoptotic cell death in CML cell lines and primary cells with the BIM deletion polymorphism. More importantly, SB939 both decreases the viability of CML cell lines and primary CML progenitors with the BIM deletion and restores TKI-sensitivity. Our results demonstrate that SB939 overcomes BIM deletion polymorphism-induced TKI resistance, and suggest that SB939 may be useful in treating CML patients with BIM deletion-associated TKI resistance. |
| Databáze: | OpenAIRE |
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