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Inhibition of MEK signaling enhances the ability of cytarabine to induce growth arrest and apoptosis of acute myelogenous leukemia cells

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Abstract

The mitogen-activated protein kinase/ERK kinase (MEK)/ERK pathway was shown to be constitutively activated in a large number of acute myelogenous leukemia (AML) cells, suggesting the important roles of this pro-survival signaling in leukemogenesis and proliferation of AML cells. This study explored the impact of the MEK inhibitor AZD6244 on the effect of cytarabien (AraC), one of the most commonly used anti-leukemia agents, to induce growth arrest and apoptosis of AML cells. AZD6244 effectively blocked AraC-induced MEK/ERK activation and enhanced its ability to induce growth arrest and apoptosis of NB4 and HL60 cells in parallel with induction of DNA damage as measured by detection of γ-H2AX by Western Blot analysis, resulting in enhanced expression of p21waf1 and downregulation of c-Myc and Bcl-xl in these cells. Enhanced induction of apoptosis mediated by combination of AZD6244 and AraC was also shown in freshly isolated AML cells (n = 3). Taken together, concomitant administration of AraC and the inhibitor of MEK/ERK signaling may be useful for treatment of individuals with AML.

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Abbreviations

AML:

Acute myelogeneous leukemia

APL:

Acute promyelocytic leukemia

HDACI:

Histone deacetylase inhibitor

ERK:

Extracellular signal-regulated kinase

MEK:

Mitogen-activated protein kinase/ERK kinase

AraC:

Cytarabine

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Acknowledgments

This work was supported in part by Grant-in-Aid from the Ministry of Education, Culture Sports, Science, and Technology of Japan (to Takayuki Ikezoe), The Kochi University President’s Discretionary Grant (to Takayuki Ikezoe), Takeda Science Foundation (to Takayuki Ikezoe), AstraZeneca Research Grant 2008 (to Takayuki Ikezoe) and Sagawa Foundation for Promotion of Cancer Research (to Takayuki Ikezoe). Chie Nishioka is grateful for a JSPS Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan

    Chie Nishioka, Takayuki Ikezoe, Jing Yang & Akihito Yokoyama

  2. Japanese Society for the Promotion of Science (JSPS), Chiyodaku, Tokyo, Japan

    Chie Nishioka

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  1. Chie Nishioka
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  2. Takayuki Ikezoe
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  4. Akihito Yokoyama
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Correspondence to Takayuki Ikezoe.

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Nishioka, C., Ikezoe, T., Yang, J. et al. Inhibition of MEK signaling enhances the ability of cytarabine to induce growth arrest and apoptosis of acute myelogenous leukemia cells. Apoptosis 14, 1108–1120 (2009). https://doi.org/10.1007/s10495-009-0372-4

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  • DOI: https://doi.org/10.1007/s10495-009-0372-4

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