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HDAC inhibitors potentiate the apoptotic effect of enzastaurin in lymphoma cells

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Abstract

Enzastaurin is an investigational PKCβ inhibitor that has growth inhibitory and pro-apoptotic effects in both B and T-cell lymphomas. We investigated the cytotoxicity and mechanisms of cell death of the combination of enzastaurin and low concentrations of histone deacetylase (HDAC) inhibitors in B-cell and T-cell lymphoma cell lines and primary lymphoma/leukemia cells. Combined enzastaurin/suberoylanilide hydroxamic acid treatment synergistically induced apoptosis in diffuse large B-cell lymphoma and T-cell lymphoma cell lines, and primary lymphoma/leukemia samples. Similarly, combined treatment of B-cell-like lymphoma cells with enzastaurin and two different HDAC inhibitors, valproic acid and (2E,4E)-6-(4-chlorophenylsulfanyl)-2,4-hexadienoic acid hydroxyamide synergistically induced apoptosis, suggesting the synergy is generalizable to other HDAC inhibitors. Our data indicate that enzastaurin/HDAC inhibitors therapy can synergistically inhibit growth and induce apoptosis in lymphoid malignancies and may be an effective therapeutic strategy. Potential mechanisms including enzastaurin mediated inhibition of HDAC inhibitor-induced compensatory survival pathways are discussed.

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Acknowledgements

The authors acknowledge Lisa Durkin for her technical expertise in cell culturing and immunostaining.

Conflict of Interest Statement

Juraj Bodo, Jan Sedlak, Jaroslaw P. Maciejewski, Alex Almasan have no financial or personal relationships with other people or organizations that could inappropriately influence this work. Eric Hsi receives research support from Eli Lilly and Company. Eli Lilly and Company had no role or input in the experimental design, data analysis, or manuscript writing.

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Authors and Affiliations

  1. Department of Clinical Pathology, L-11, Institute of Pathology and Laboratory Medicine, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH, 44195, USA

    Juraj Bodo & Eric D. Hsi

  2. Department of Tumor Immunology, Cancer Research Institute, Bratislava, Slovak Republic

    Jan Sedlak

  3. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Jaroslaw P. Maciejewski

  4. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Alex Almasan

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  1. Juraj Bodo
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Correspondence to Eric D. Hsi.

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Bodo, J., Sedlak, J., Maciejewski, J.P. et al. HDAC inhibitors potentiate the apoptotic effect of enzastaurin in lymphoma cells. Apoptosis 16, 914–923 (2011). https://doi.org/10.1007/s10495-011-0617-x

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