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

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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.

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Author and article information

Contributors

Persio Dello Sbarba: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 27 January 2016

Publication date Collection: 2016

Volume: 11

Issue: 1

Electronic Location Identifier: e0148093

Affiliations

[1 ]Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

[2 ]Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan

[3 ]Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, Taiwan

Università degli Studi di Firenze, ITALY

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: HMH. Performed the experiments: SMW FHL YLL. Analyzed the data: SMW FHL HMH. Contributed reagents/materials/analysis tools: HMH. Wrote the paper: HMH. Obtained permission for use of cell line: SMW FHL HMH.

* E-mail: cmbhhm@ 123456tmu.edu.tw

Article

Publisher ID: PONE-D-15-38955

DOI: 10.1371/journal.pone.0148093

PMC ID: 4729476

PubMed ID: 26815740

SO-VID: 5d6a89a5-2c36-4ca8-819b-1da846df635c

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 3 September 2015

Date accepted : 13 January 2016

Page count

Figures: 8, Tables: 0, Pages: 16

Funding

This work was supported by grants from the Ministry of Science and Technology (MOST 104-2320-B-038-028), Taiwan, ROC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability All relevant data are within the paper.

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