title: Celecoxib suppresses autophagy and enhances cytotoxicity of imatinib in imatinib-resistant chronic myeloid leukemia cells.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Blood Transfusion, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.|Department of Hematology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Hematology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Oncology in South China, Department of VIP Region, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Shou-Sheng
authors.initials: SS
authors.lastname: Liu
authors.affiliation: Department of Hematology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Fang
authors.affiliation: Department of Blood Transfusion, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Cancer Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Xu-Bin
authors.initials: XB
authors.lastname: Deng
authors.affiliation: Department of Hematology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.|Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zi-Jie
authors.initials: ZJ
authors.lastname: Long
authors.affiliation: Department of Hematology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.|Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Blood Transfusion, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. lindongjun0168@163.com.|Department of Hematology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. lindongjun0168@163.com.|Institute of Hematology, Sun Yat-sen University, Guangzhou, China. lindongjun0168@163.com.
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Lin
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000068579:Celecoxib / Q000494:pharmacology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D009367:Neoplasm Staging
chemical_list: D000068877:Imatinib Mesylate; D000068579:Celecoxib
keywords: Autophagy; CML; Celecoxib; Imatinib