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, A. Illés, Yuan Ji, Anas Younes

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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 IC 50 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
JournalExperimental Hematology
Volume39
Issue number10
DOIs
Publication statusPublished - Oct 2011

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Histone Deacetylase Inhibitors
Hodgkin Disease
Apoptosis
Chemokines
Testicular Neoplasms
Cytokines
Cell Line
Cell Death
Down-Regulation
Chemokine CCL17
X-Linked Inhibitor of Apoptosis Protein
entinostat
Chemokine CXCL10
Antigens
Interleukin-13
Propidium
Annexin A5
Interleukin-12
Acetylation
Reverse Transcriptase Polymerase Chain Reaction

ASJC Scopus subject areas

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

Cite this

The histone deacetylase inhibitor entinostat (sndx-275) induces apoptosis in hodgkin lymphoma cells and synergizes with bcl-2 family inhibitors. / Jóna, Ádám; Khaskhely, Noor; Buglio, Daniela; Shafer, Jessica A.; Derenzini, Enrico; Bollard, Catherine M.; Medeiros, L. Jeffrey; Illés, A.; Ji, Yuan; Younes, Anas.

In: Experimental Hematology, Vol. 39, No. 10, 10.2011.

Research output: Contribution to journalArticle

Jóna, Ádám ; Khaskhely, Noor ; Buglio, Daniela ; Shafer, Jessica A. ; Derenzini, Enrico ; Bollard, Catherine M. ; Medeiros, L. Jeffrey ; Illés, A. ; Ji, Yuan ; Younes, Anas. / The histone deacetylase inhibitor entinostat (sndx-275) induces apoptosis in hodgkin lymphoma cells and synergizes with bcl-2 family inhibitors. In: Experimental Hematology. 2011 ; Vol. 39, No. 10.
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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 IC 50 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.",
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AU - Jóna, Ádám

AU - Khaskhely, Noor

AU - Buglio, Daniela

AU - Shafer, Jessica A.

AU - Derenzini, Enrico

AU - Bollard, Catherine M.

AU - Medeiros, L. Jeffrey

AU - Illés, A.

AU - Ji, Yuan

AU - Younes, Anas

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N2 - 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 IC 50 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.

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