Celecoxib suppresses autophagy and enhances cytotoxicity of imatinib in imatinib-resistant chronic myeloid leukemia cells.

Ying Lu,Ying Lu,Xu-Bin Deng,Ling-Ling Liu,Zi-Jie Long,Quentin Liu,Quentin Liu,Zhi-Gang Fang,Shou-Sheng Liu,Ling-Ling Liu,Shou-Sheng Liu,Yong Zou,Yong Zou,Dong-Jun Lin,Dong-Jun Lin,Zhi-Gang Fang

doi:10.1186/s12967-016-1012-8

Abstract

BackgroundChronic 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.MethodsThe 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.ResultsIn 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.ConclusionsThese 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 materialThe online version of this article (doi:10.1186/s12967-016-1012-8) contains supplementary material, which is available to authorized users.

Highlights

Chronic myelogenous leukemia (CML) is a hematological stem cell disorder
We examined the effect of celecoxib on cell proliferation, necrosis, apoptosis and autophagy in CML cell lines KBM5 and KBM5-T315I
Cytotoxic effect of celecoxib on human CML cells First, the cytotoxic effect of celecoxib and imatinib on CML cells was measured by MTT assay

Summary

Introduction

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. Chronic myelogenous leukemia (CML) is a hematological stem cell disorder responsible for 15–20 % of newly diagnosed leukemia in adults. There are only few studies on the effects of celecoxib on hematological malignancies These studies revealed that celecoxib could inhibit the proliferation of lymphoma, acute leukemia or CML cells [18,19,20,21]. Celecoxib was reported to have anti-tumor effects on K562 and HL-60 leukemia cells demonstrated by cell-cycle arrest and cell apoptosis and the effects were synergistic with other chemotherapy medicines [19, 21]. The molecular mechanism of these anti-tumor effects has not been well elucidated

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