Celecoxib suppresses autophagy and enhances cytotoxicity of imatinib in imatinib-resistant chronic myeloid leukemia cells
| Autor: | Ling Ling Liu, Zi Jie Long, Quentin Liu, Yong Zou, Ying Lu, Zhi Gang Fang, Shou Sheng Liu, Dong Jun Lin, Xu Bin Deng |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
musculoskeletal diseases Adult Male Apoptosis Pharmacology Gene mutation General Biochemistry Genetics and Molecular Biology 03 medical and health sciences chemistry.chemical_compound Necrosis 0302 clinical medicine hemic and lymphatic diseases Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive medicine Autophagy Humans MTT assay heterocyclic compounds Propidium iodide skin and connective tissue diseases neoplasms CML Neoplasm Staging Medicine(all) Biochemistry Genetics and Molecular Biology(all) business.industry Research Imatinib General Medicine Cell cycle Middle Aged medicine.disease G1 Phase Cell Cycle Checkpoints 030104 developmental biology chemistry Celecoxib Drug Resistance Neoplasm 030220 oncology & carcinogenesis Imatinib Mesylate Female business Lysosomes Tyrosine kinase Chronic myelogenous leukemia medicine.drug |
| Zdroj: | Journal of Translational Medicine |
| ISSN: | 1479-5876 |
| Popis: | Background Chronic myelogenous leukemia (CML) is a hematological stem cell disorder. Tyrosine kinase inhibitors (TKIs) are the standard treatments for CML, but a number of patients fail to respond effectively due to gene mutations. Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, has been shown to have anti-tumor effect on solid tumor whereas the anti-CML effect and its underlying mechanism have not been completely elucidated. Methods The cytotoxic effects of celecoxib and/or imatinib were evaluated by MTT assay. Cell cycle distribution was examined by propidium iodide (PI) assay. Apoptosis or necrosis was analyzed by Annexin-V/PI, Hoechst 33342 staining and Western blot assays. Autophagy suppression effect of celecoxib was examined by Western blot and LysoTracker probe labelling. Lysosensor probe labelling was used to detect the effect of celecoxib on the lysosomal function. Results In this study, we found that celecoxib had therapy efficacy in KBM5 and imatinib-resistant KBM5-T315I CML cell lines. Celecoxib caused significant cytotoxic effect in both cell lines, especially in KBM5-T315I cells exposed to celecoxib for 72 h. Moreover, celecoxib induced necrosis and apoptosis while inhibited autophagy in CML cell lines and patient samples. Furthermore, this study demonstrated that celecoxib prevented the autophagic flux by inhibiting lysosome function. Celecoxib was tested in combination with imatinib, demonstrating that celecoxib could strengthen the cytotoxicity of imatinib in imatinib-resistant CML cells. Conclusions These findings showed that celecoxib had therapy efficacy on CML cells. And it is first time to demonstrate that celecoxib is an autophagy suppresser and a combination of celecoxib and imatinib might be a promising new therapeutic strategy for imatinib-resistant CML cells. Electronic supplementary material The online version of this article (doi:10.1186/s12967-016-1012-8) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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