Lapatinib Induces Autophagy, Apoptosis and Megakaryocytic Differentiation in Chronic Myelogenous Leukemia K562 Cells

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Abstract

Lapatinib is an oral, small-molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptors (EGFR, or ErbB/Her) in solid tumors. Little is known about the effect of lapatinib on leukemia. Using human chronic myelogenous leukemia (CML) K562 cells as an experimental model, we found that lapatinib simultaneously induced morphological changes resembling apoptosis, autophagy, and megakaryocytic differentiation. Lapatinib-induced apoptosis was accompanied by a decrease in mitochondrial transmembrane potential and was attenuated by the pancaspase inhibitor z-VAD-fmk, indicating a mitochondria-mediated and caspase-dependent pathway. Lapatinib-induced autophagic cell death was verified by LC3-II conversion, and upregulation of Beclin-1. Further, autophagy inhibitor 3-methyladenine as well as autophagy-related proteins Beclin-1 (ATG6), ATG7, and ATG5 shRNA knockdown rescued the cells from lapatinib-induced growth inhibition. A moderate number of lapatinib-treated K562 cells exhibited features of megakaryocytic differentiation. In summary, lapatinib inhibited viability and induced multiple cellular events including apoptosis, autophagic cell death, and megakaryocytic differentiation in human CML K562 cells. This distinct activity of lapatinib against CML cells suggests potential for lapatinib as a therapeutic agent for treatment of CML. Further validation of lapatinib activity in vivo is warranted.

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Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009.

G Kroemer, L Galluzzi, P Vandenabeele … (2009)

Different types of cell death are often defined by morphological criteria, without a clear reference to precise biochemical mechanisms. The Nomenclature Committee on Cell Death (NCCD) proposes unified criteria for the definition of cell death and of its different morphologies, while formulating several caveats against the misuse of words and concepts that slow down progress in the area of cell death research. Authors, reviewers and editors of scientific periodicals are invited to abandon expressions like 'percentage apoptosis' and to replace them with more accurate descriptions of the biochemical and cellular parameters that are actually measured. Moreover, at the present stage, it should be accepted that caspase-independent mechanisms can cooperate with (or substitute for) caspases in the execution of lethal signaling pathways and that 'autophagic cell death' is a type of cell death occurring together with (but not necessarily by) autophagic vacuolization. This study details the 2009 recommendations of the NCCD on the use of cell death-related terminology including 'entosis', 'mitotic catastrophe', 'necrosis', 'necroptosis' and 'pyroptosis'.

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Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells.

Gottfried Konecny, Mark Pegram, Natarajan Venkatesan … (2006)

Lapatinib (GW572016) is a selective inhibitor of both epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases. Here, we explore the therapeutic potential of lapatinib by testing its effect on tumor cell growth in a panel of 31 characterized human breast cancer cell lines, including trastuzumab-conditioned HER-2-positive cell lines. We further characterize its activity in combination with trastuzumab and analyze whether EGFR and HER-2 expression or changes induced in the activation of EGFR, HER-2, Raf, AKT, or extracellular signal-regulated kinase (ERK) are markers of drug activity. We report that concentration-dependent antiproliferative effects of lapatinib were seen in all breast cancer cell lines tested but varied significantly between individual cell lines with up to 1,000-fold difference in the IC(50)s (range, 0.010-18.6 micromol/L). Response to lapatinib was significantly correlated with HER-2 expression and its ability to inhibit HER-2, Raf, AKT, and ERK phosphorylation. Long-term in vivo lapatinib studies were conducted with human breast cancer xenografts in athymic mice. Treatment over 77 days resulted in a sustained and significant reduction in xenograft volume compared with untreated controls. For the combination of lapatinib plus trastuzumab, synergistic drug interactions were observed in four different HER-2-overexpressing cell lines. Moreover, lapatinib retained significant in vitro activity against cell lines selected for long-term outgrowth (>9 months) in trastuzumab-containing (100 microg/mL) culture medium. These observations provide a clear biological rationale to test lapatinib as a single agent or in combination with trastuzumab in HER-2-overexpressing breast cancer and in patients with clinical resistance to trastuzumab.

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Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes.

L Galluzzi, S A Aaronson, J. Abrams … (2009)

Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases. Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies. It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios. Thus far, dozens of methods have been proposed to quantify cell death-related parameters. However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate. Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls. These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise. Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells.

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Author and article information

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: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

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

ISSN (Electronic): 1932-6203

Publication date Collection: 2011

Publication date (Electronic): 22 December 2011

Volume: 6

Issue: 12

Electronic Location Identifier: e29014

Affiliations

[1 ]Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, Taiwan

[2 ]Department of Medical Research, China Medical University Hospital, Taichung, Taiwan

[3 ]Graduate Institute of Chinese Medical Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan

[4 ]Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan

[5 ]Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan

[6 ]Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

[7 ]Institute of Pharmacology, Taipei Medical University, Taipei, Taiwan

University of Chicago, United States of America

Author notes

* E-mail: chenmdphd@ 123456yahoo.com

Conceived and designed the experiments: HH YJC. Performed the experiments: HH YCC KY HP SS. Analyzed the data: HH YCC YH KY HP. Contributed reagents/materials/analysis tools: HH YH YJC. Wrote the paper: HH YJC.

Article

Publisher ID: PONE-D-11-05668

DOI: 10.1371/journal.pone.0029014

PMC ID: 3245247

PubMed ID: 22216158

SO-VID: 3f1d5fe5-841c-46a2-8cf3-d566ae8cf4ee

Copyright © Huang et al. 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.

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Date received : 27 March 2011

Date accepted : 17 November 2011

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Pages: 10

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Lapatinib Induces Autophagy, Apoptosis and Megakaryocytic Differentiation in Chronic Myelogenous Leukemia K562 Cells

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Most cited references 45

Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009.

Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells.

Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes.

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