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Lymphoma

A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas

Leukemia volume 22, pages 1026–1034 (2008)Cite this article

Abstract

We have developed a potent, histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 with >200-fold selectivity over the other HDAC isoforms. PCI-34051 induces caspase-dependent apoptosis in cell lines derived from T-cell lymphomas or leukemias, but not in other hematopoietic or solid tumor lines. Unlike broad-spectrum HDAC inhibitors, PCI-34051 does not cause detectable histone or tubulin acetylation. Cells defective in T-cell receptor signaling were still sensitive to PCI-34051-induced apoptosis, whereas a phospholipase C-γ1 (PLCγ1)-defective line was resistant. Jurkat cells showed a dose-dependent decrease in PCI-34051-induced apoptosis upon treatment with a PLC inhibitor U73122, but not with an inactive analog. We found that rapid intracellular calcium mobilization from endoplasmic reticulum (ER) and later cytochrome c release from mitochondria are essential for the apoptotic mechanism. The rapid Ca2+ flux was dependent on PCI-34051 concentration, and was blocked by the PLC inhibitor U73122. Further, apoptosis was blocked by Ca2+ chelators (BAPTA) and enhanced by Ca2+ effectors (thapsigargin), supporting this model. These studies show that HDAC8-selective inhibitors have a unique mechanism of action involving PLCγ1 activation and calcium-induced apoptosis, and could offer benefits including a greater therapeutic index for treating T-cell malignancies.

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Authors and Affiliations

  1. Department of Cancer Biology, Pharmacyclics Inc., Sunnyvale, CA, USA

    S Balasubramanian, J Ramos, M Sirisawad & J J Buggy

  2. Department of Chemistry, Pharmacyclics Inc., Sunnyvale, CA, USA

    W Luo & E Verner

Authors
  1. S Balasubramanian
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Correspondence to S Balasubramanian.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Balasubramanian, S., Ramos, J., Luo, W. et al. A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas. Leukemia 22, 1026–1034 (2008). https://doi.org/10.1038/leu.2008.9

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