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Chronic Myeloid Leukemia, BCR/ABL Studies and Myelo Proliferative Disorders

Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells

Leukemia volume 19, pages 1579–1589 (2005)Cite this article

A Retraction to this article was published on 08 April 2016

Abstract

Interactions between the histone deacetylase inhibitor SAHA and the pharmacologic MEK1/2 inhibitor PD184352 were examined in Bcr/Abl+ human leukemia cells. Coadministration of minimally toxic concentrations of SAHA (or sodium butyrate) and PD184352 (or U0126) resulted in a synergistic increase in mitochondrial damage, caspase activation, and apoptosis in K562 and LAMA 84 cells. Similar interactions were observed in CD34+ cells from two patients with CML and in imatinib mesylate-resistant K562 cells but not in normal human CD34+ bone marrow cells. These events were associated with a marked increase in ROS generation, inactivation of ERK and Akt, downregulation of p21CIP1, Bcr/Abl, and cyclin D1, and activation of JNK. Of these events, ROS generation, ERK inactivation, and cytochrome c/AIF release were largely caspase-independent, whereas the other phenomena displayed varying degrees of caspase-dependence. Using pharmacologic and genetic approaches, generation of ROS, p21CIP1 downregulation, and inactivation of Akt and MEK were found to play significant functional roles in SAHA/PD184352-mediated lethality, whereas JNK activation and Raf-1 downregulation were determined to represent secondary events. These findings indicate that interruption of the MEK/ERK pathway substantially lowers the threshold for HDAC inhibitor-mediated oxidative injury, mitochondrial dysfunction, and apoptosis, suggesting that this approach warrants further examination in Bcr/Abl+-related malignancies.

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Acknowledgements

This work was supported by awards CA63753, CA93738, and CA 100866, CA88906, CA72955 from the NIH, A Translational Research Award from the Leukemia and Lymphoma Society of America (6045-03), an award from the Department of Defense (DAMD-17-03-1-0209), an award from the V Foundation, and by the Universal Professorship (to PD).

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  1. C Yu and G Dasmahapatra: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA

    C Yu, G Dasmahapatra & S Grant

  2. Department of Biochemistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA

    P Dent & S Grant

  3. Department of Pharmacology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA

    S Grant

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Correspondence to S Grant.

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Yu, C., Dasmahapatra, G., Dent, P. et al. Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells. Leukemia 19, 1579–1589 (2005). https://doi.org/10.1038/sj.leu.2403868

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