MPT0B169, a New Antitubulin Agent, Inhibits Bcr-Abl Expression and Induces Mitochondrion-Mediated Apoptosis in Nonresistant and Imatinib-Resistant Chronic Myeloid Leukemia Cells.

Shuit-Mun Wong,Huei-Mei Huang,Yueh-Lun Lee,Fu-Hwa Liu,Persio Dello Sbarba

doi:10.1371/journal.pone.0148093

Shuit-Mun Wong, Huei-Mei Huang + Show 3 more

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https://doi.org/10.1371/journal.pone.0148093

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Journal: PloS one	Publication Date: Jan 27, 2016
Citations: 6	License type: CC BY 4.0

Affiliation: Taipei Medical University

Abstract

Chronic myeloid leukemia (CML) is a clonal disorder of hematopoietic stem/progenitor cells that is caused by the Bcr-Abl oncoprotein. Clinical resistance to the Bcr-Abl inhibitor imatinib is a critical problem in treating CML. This study investigated the antitumor effect and mechanism of MPT0B169, a new antitubulin agent, in K562 CML cells and their derived imatinib-resistant cells, IMR2 and IMR3. IMR2 and IMR3 cells showed complete resistance to imatinib-induced growth inhibition and apoptosis. Resistance involved ERK1/2 overactivation and MDR1 overexpression. MPT0B169 inhibited the growth of K562, IMR2, and IMR3 cells in a dose- and time-dependent manner. MPT0B169 substantially inhibited the mRNA and protein levels of Bcr-Abl, followed by its downstream pathways including Akt, ERK1/2, and STAT3 in these cells. MPT0B169 treatment resulted in a decrease in the polymer form of tubulin according to Western blot analysis. It triggered cell cycle arrest at the G2/M phase before apoptosis, which was related to the upregulation of the mitotic marker MPM2 and the cyclin B1 level, and a change in the phosphorylation of Cdk1. MPT0B169 induced apoptosis in nonresistant and imatinib-resistant cells via a mitochondrion-mediated caspase pathway. Further study showed that the agent led to a decrease in the antiapoptotic proteins Bcl-2, Bcl-xL, and Mcl-1 and an increase in the apoptotic protein Bax. Taken together, our results suggest that MPT0B169 might be a promising agent for overcoming imatinib resistance in CML cells.

Highlights

Chronic myeloid leukemia (CML) is a malignant disorder of hematopoietic stem/progenitor cells characterized by the reciprocal translocation between chromosomes 9 and 22 t(9;22) leading to the formation of the Philadelphia (Ph) chromosome [1]
Our findings indicate that MPT0B169, a new antitubulin agent, inhibits Bcr-Abl expression and induces cell cycle arrest at the G2/M phase, resulting in growth inhibition and mitochondrion-associated apoptosis in nonresistant and imatinib-resistant CML cells
Activation of ERK2 was found to be responsible for imatinib resistance in CML cell lines and a CML patient [16]

Summary

Introduction

Chronic myeloid leukemia (CML) is a malignant disorder of hematopoietic stem/progenitor cells characterized by the reciprocal translocation between chromosomes 9 and 22 t(9;22) leading to the formation of the Philadelphia (Ph) chromosome [1]. Bcr-Abl protein, a constitutively activated tyrosine kinase, is the product of the chimeric Bcr-Abl fusion gene on the Ph chromosome [1]. Bcr-Abl constitutively activates downstream effector pathways that stimulate cell proliferation and protect cells from apoptosis, such as Akt, ERK1/2, and STAT3 [2,3]. Imatinib (STI571, Gleevec), a Bcr-Abl tyrosine kinase inhibitor, is highly effective and is currently the first-line therapy for CML [4]. Imatinib has improved clinical outcomes in the chronic phase of CML, drug resistance emerged in some patients, especially in the accelerated phase and blast crisis. Second- and third-generation inhibitors are effective against most imatinib-resistant (IMR) CML, but some patients become resistant to these drugs [8]. There is still an urgent need to develop novel agents that can be used to overcome Bcr-Abl inhibitor resistance

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