The histone deacetylase inhibitor entinostat (sndx-275) induces apoptosis in hodgkin lymphoma cells and synergizes with bcl-2 family inhibitors

Ádám Jóna, Noor Khaskhely, Daniela Buglio, Jessica A. Shafer, Enrico Derenzini, Catherine M. Bollard, L. Jeffrey Medeiros, Árpád Illés, Yuan Ji, Anas Younes

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34 Citations (Scopus)

Abstract

Objective: Based on promising in vitro and in vivo activity of several histone deacetylase inhibitors in Hodgkin lymphoma (HL), we investigated SNDX-275, an oral class 1 isoform-selective histone deacetylase inhibitors in HL-derived cell lines. Materials and Methods: Proliferation and cell death were examined by MTS assay, Annexin V/propidium iodide, and fluorescence-activated cell sorting analysis. Gene and protein expression were measured by reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemical analysis. A multiplex assay was used to determine cytokines and chemokines. Results: SNDX-275 induced cell death in a dose- and time-dependent manner with an IC50 at the sub- and lower micromolar range at 72 hours. At the molecular level, SNDX-275 increased histone H3 acetylation, upregulated p21 expression, and activated the intrinsic apoptosis pathway by downregulating the X-linked inhibitor of apoptosis protein. SNDX-275 downregulated expression of antiapoptotic Bcl-2 and Bcl-xL proteins without altering Mcl-1 or Bax levels. Combination studies demonstrated that two Bcl-2 inhibitors (ABT-737 and obatoclax) significantly enhanced the effect of SNDX-275. SNDX-275 modulated the level of several cytokines and chemokines, including interleukin-12 p40-70, interferon-inducible protein-10, RANTES (regulated on activation, normal T expressed and secreted), interleukin-13, interleukin-4, and thymus and activation-regulated chemokine and variably induced the cancer/testis antigen expression of MAGE-A4 and survivin in HL cell lines. Conclusions: SNDX-275 has antiproliferative activity in HL cell lines, involving several mechanisms: induction of apoptosis, regulation of cytokines and chemokines, and alteration of cancer/testis antigens. Clinical investigation of SNDX-275 alone or in combination with Bcl-2 inhibitors is warranted in patients with HL. Phase 2 studies with SNDX-275 in HL are ongoing, and future clinical studies should investigate combinations with SNDX-275.

Original languageEnglish
Pages (from-to)1007-1017.e1
JournalExperimental Hematology
Volume39
Issue number10
DOIs
Publication statusPublished - Oct 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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    Jóna, Á., Khaskhely, N., Buglio, D., Shafer, J. A., Derenzini, E., Bollard, C. M., Medeiros, L. J., Illés, Á., Ji, Y., & Younes, A. (2011). The histone deacetylase inhibitor entinostat (sndx-275) induces apoptosis in hodgkin lymphoma cells and synergizes with bcl-2 family inhibitors. Experimental Hematology, 39(10), 1007-1017.e1. https://doi.org/10.1016/j.exphem.2011.07.002