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

doi:10.1016/j.exphem.2011.07.002

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^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

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 language	English (US)
Pages (from-to)	1007-1017.e1
Journal	Experimental Hematology
Volume	39
Issue number	10
DOIs	https://doi.org/10.1016/j.exphem.2011.07.002
State	Published - Oct 2011

Funding

This research is supported in part by the National Institutes of Health (NIH) through M.D. Anderson’s Cancer Center Support Grant CA016672 , NCI Lymphoma SPORE grant 1P50CA136411-01A1 , The Living Legend Fund, and the Prince Fund for Lymphoma (Anas Younes), by NIH grant P50 CA126752 , the Gillson Longenbaugh Foundation, and the M.D. Anderson Foundation (Catherine M. Bollard), and by The Hungarian American Enterprise Scholarship Fund (Ádám Jóna).

ASJC Scopus subject areas

Molecular Biology
Hematology
Genetics
Cell Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.exphem.2011.07.002

Cite this

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

@article{68abee423cd84951803665e184107a91,

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

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.",

author = "{\'A}d{\'a}m J{\'o}na and Noor Khaskhely and Daniela Buglio and Shafer, {Jessica A.} and Enrico Derenzini and Bollard, {Catherine M.} and Medeiros, {L. Jeffrey} and {\'A}rp{\'a}d Ill{\'e}s and Yuan Ji and Anas Younes",

note = "Funding Information: This research is supported in part by the National Institutes of Health (NIH) through M.D. Anderson{\textquoteright}s Cancer Center Support Grant CA016672 , NCI Lymphoma SPORE grant 1P50CA136411-01A1 , The Living Legend Fund, and the Prince Fund for Lymphoma (Anas Younes), by NIH grant P50 CA126752 , the Gillson Longenbaugh Foundation, and the M.D. Anderson Foundation (Catherine M. Bollard), and by The Hungarian American Enterprise Scholarship Fund ({\'A}d{\'a}m J{\'o}na). ",

year = "2011",

month = oct,

doi = "10.1016/j.exphem.2011.07.002",

language = "English (US)",

volume = "39",

pages = "1007--1017.e1",

journal = "Experimental Hematology",

issn = "0301-472X",

publisher = "Elsevier Inc.",

number = "10",

}

Jóna, Á, Khaskhely, N, Buglio, D, Shafer, JA, Derenzini, E, Bollard, CM, Medeiros, LJ, 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, vol. 39, no. 10, pp. 1007-1017.e1. https://doi.org/10.1016/j.exphem.2011.07.002

TY - JOUR

T1 - The histone deacetylase inhibitor entinostat (sndx-275) induces apoptosis in hodgkin lymphoma cells and synergizes with bcl-2 family inhibitors

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, Árpád

AU - Ji, Yuan

AU - Younes, Anas

N1 - Funding Information: This research is supported in part by the National Institutes of Health (NIH) through M.D. Anderson’s Cancer Center Support Grant CA016672 , NCI Lymphoma SPORE grant 1P50CA136411-01A1 , The Living Legend Fund, and the Prince Fund for Lymphoma (Anas Younes), by NIH grant P50 CA126752 , the Gillson Longenbaugh Foundation, and the M.D. Anderson Foundation (Catherine M. Bollard), and by The Hungarian American Enterprise Scholarship Fund (Ádám Jóna).

PY - 2011/10

Y1 - 2011/10

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 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80052840489&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052840489&partnerID=8YFLogxK

U2 - 10.1016/j.exphem.2011.07.002

DO - 10.1016/j.exphem.2011.07.002

M3 - Article

C2 - 21767511

AN - SCOPUS:80052840489

SN - 0301-472X

VL - 39

SP - 1007-1017.e1

JO - Experimental Hematology

JF - Experimental Hematology

IS - 10

ER -

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

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this