Romidepsin and belinostat synergize the antineoplastic effect of bortezomib in mantle cell lymphoma

Luca Paoluzzi, Luigi Scotto, Enrica Marchi, Jasmine Zain, Venkatraman E. Seshan, Owen A. O'Connor

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Purpose: Romidepsin and belinostat are inhibitors of histone deacetylases (HDACI). HDACIs are known to induce cell death in malignant cells through multiple mechanisms, including upregulation of death receptors and induction of cell cycle arrest. They are also known to be prodifferentiating. Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma characterized by the t(11;14) (q13;q32) translocation leading to the overexpression of cyclin D1. Experimental Design: Assays for cytotoxicty including mathematical analysis for synergism, flow-cytometry, immunoblottings, and a xenograft severe combined immunodeficient beige mouse model were used to explore the in vitro and in vivo activity of romidepsin and/or belinostat alone or in combination with the proteasome inhibitor bortezomib in MCL. Results: In vitro, romidepsin and belinostat exhibited concentration-dependent cytotoxicity against a panel of MCL cell lines. Both HDACI showed strong synergism when combined with the proteasome inhibitor bortezomib in MCL. An HDACI plus bortezomib also induced potent mitochondrial membrane depolarization and apoptosis, whereas no significant apoptosis was observed in peripheral blood mononuclear cells from healthy donors with the combination. These events were associated with a decrease in cyclin D1 and Bcl-XL, and an increase in accumulation of acetylated histone H3, acetylated α-tubulin, and Noxa in cell lines. In a severe combined immunodeficient beige mouse model of MCL, the addition of belinostat to bortezomib enhanced efficacy compared with either drug alone. Conclusions: Collectively, these data strongly suggest that HDACI such as romidepsin or belinostat in combination with a proteasome inhibitor could represent a novel and rationale platform for the treatment of MCL.

Original languageEnglish (US)
Pages (from-to)554-565
Number of pages12
JournalClinical Cancer Research
Volume16
Issue number2
DOIs
StatePublished - Jan 15 2010
Externally publishedYes

Fingerprint

Mantle-Cell Lymphoma
Antineoplastic Agents
Proteasome Inhibitors
SCID Mice
Cyclin D1
Noxae
Apoptosis
Cell Line
Death Domain Receptors
Histone Deacetylases
Mitochondrial Membranes
Tubulin
Cell Cycle Checkpoints
Immunoblotting
Heterografts
Histones
Non-Hodgkin's Lymphoma
Bortezomib
romidepsin
belinostat

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Romidepsin and belinostat synergize the antineoplastic effect of bortezomib in mantle cell lymphoma. / Paoluzzi, Luca; Scotto, Luigi; Marchi, Enrica; Zain, Jasmine; Seshan, Venkatraman E.; O'Connor, Owen A.

In: Clinical Cancer Research, Vol. 16, No. 2, 15.01.2010, p. 554-565.

Research output: Contribution to journalArticle

Paoluzzi, Luca ; Scotto, Luigi ; Marchi, Enrica ; Zain, Jasmine ; Seshan, Venkatraman E. ; O'Connor, Owen A. / Romidepsin and belinostat synergize the antineoplastic effect of bortezomib in mantle cell lymphoma. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 2. pp. 554-565.
@article{f2c96a1bdb894299bebc202a7ff3a7d9,
title = "Romidepsin and belinostat synergize the antineoplastic effect of bortezomib in mantle cell lymphoma",
abstract = "Purpose: Romidepsin and belinostat are inhibitors of histone deacetylases (HDACI). HDACIs are known to induce cell death in malignant cells through multiple mechanisms, including upregulation of death receptors and induction of cell cycle arrest. They are also known to be prodifferentiating. Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma characterized by the t(11;14) (q13;q32) translocation leading to the overexpression of cyclin D1. Experimental Design: Assays for cytotoxicty including mathematical analysis for synergism, flow-cytometry, immunoblottings, and a xenograft severe combined immunodeficient beige mouse model were used to explore the in vitro and in vivo activity of romidepsin and/or belinostat alone or in combination with the proteasome inhibitor bortezomib in MCL. Results: In vitro, romidepsin and belinostat exhibited concentration-dependent cytotoxicity against a panel of MCL cell lines. Both HDACI showed strong synergism when combined with the proteasome inhibitor bortezomib in MCL. An HDACI plus bortezomib also induced potent mitochondrial membrane depolarization and apoptosis, whereas no significant apoptosis was observed in peripheral blood mononuclear cells from healthy donors with the combination. These events were associated with a decrease in cyclin D1 and Bcl-XL, and an increase in accumulation of acetylated histone H3, acetylated α-tubulin, and Noxa in cell lines. In a severe combined immunodeficient beige mouse model of MCL, the addition of belinostat to bortezomib enhanced efficacy compared with either drug alone. Conclusions: Collectively, these data strongly suggest that HDACI such as romidepsin or belinostat in combination with a proteasome inhibitor could represent a novel and rationale platform for the treatment of MCL.",
author = "Luca Paoluzzi and Luigi Scotto and Enrica Marchi and Jasmine Zain and Seshan, {Venkatraman E.} and O'Connor, {Owen A.}",
year = "2010",
month = "1",
day = "15",
doi = "10.1158/1078-0432.CCR-09-1937",
language = "English (US)",
volume = "16",
pages = "554--565",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - Romidepsin and belinostat synergize the antineoplastic effect of bortezomib in mantle cell lymphoma

AU - Paoluzzi, Luca

AU - Scotto, Luigi

AU - Marchi, Enrica

AU - Zain, Jasmine

AU - Seshan, Venkatraman E.

AU - O'Connor, Owen A.

PY - 2010/1/15

Y1 - 2010/1/15

N2 - Purpose: Romidepsin and belinostat are inhibitors of histone deacetylases (HDACI). HDACIs are known to induce cell death in malignant cells through multiple mechanisms, including upregulation of death receptors and induction of cell cycle arrest. They are also known to be prodifferentiating. Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma characterized by the t(11;14) (q13;q32) translocation leading to the overexpression of cyclin D1. Experimental Design: Assays for cytotoxicty including mathematical analysis for synergism, flow-cytometry, immunoblottings, and a xenograft severe combined immunodeficient beige mouse model were used to explore the in vitro and in vivo activity of romidepsin and/or belinostat alone or in combination with the proteasome inhibitor bortezomib in MCL. Results: In vitro, romidepsin and belinostat exhibited concentration-dependent cytotoxicity against a panel of MCL cell lines. Both HDACI showed strong synergism when combined with the proteasome inhibitor bortezomib in MCL. An HDACI plus bortezomib also induced potent mitochondrial membrane depolarization and apoptosis, whereas no significant apoptosis was observed in peripheral blood mononuclear cells from healthy donors with the combination. These events were associated with a decrease in cyclin D1 and Bcl-XL, and an increase in accumulation of acetylated histone H3, acetylated α-tubulin, and Noxa in cell lines. In a severe combined immunodeficient beige mouse model of MCL, the addition of belinostat to bortezomib enhanced efficacy compared with either drug alone. Conclusions: Collectively, these data strongly suggest that HDACI such as romidepsin or belinostat in combination with a proteasome inhibitor could represent a novel and rationale platform for the treatment of MCL.

AB - Purpose: Romidepsin and belinostat are inhibitors of histone deacetylases (HDACI). HDACIs are known to induce cell death in malignant cells through multiple mechanisms, including upregulation of death receptors and induction of cell cycle arrest. They are also known to be prodifferentiating. Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma characterized by the t(11;14) (q13;q32) translocation leading to the overexpression of cyclin D1. Experimental Design: Assays for cytotoxicty including mathematical analysis for synergism, flow-cytometry, immunoblottings, and a xenograft severe combined immunodeficient beige mouse model were used to explore the in vitro and in vivo activity of romidepsin and/or belinostat alone or in combination with the proteasome inhibitor bortezomib in MCL. Results: In vitro, romidepsin and belinostat exhibited concentration-dependent cytotoxicity against a panel of MCL cell lines. Both HDACI showed strong synergism when combined with the proteasome inhibitor bortezomib in MCL. An HDACI plus bortezomib also induced potent mitochondrial membrane depolarization and apoptosis, whereas no significant apoptosis was observed in peripheral blood mononuclear cells from healthy donors with the combination. These events were associated with a decrease in cyclin D1 and Bcl-XL, and an increase in accumulation of acetylated histone H3, acetylated α-tubulin, and Noxa in cell lines. In a severe combined immunodeficient beige mouse model of MCL, the addition of belinostat to bortezomib enhanced efficacy compared with either drug alone. Conclusions: Collectively, these data strongly suggest that HDACI such as romidepsin or belinostat in combination with a proteasome inhibitor could represent a novel and rationale platform for the treatment of MCL.

UR - http://www.scopus.com/inward/record.url?scp=74549173443&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=74549173443&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-09-1937

DO - 10.1158/1078-0432.CCR-09-1937

M3 - Article

C2 - 20068080

AN - SCOPUS:74549173443

VL - 16

SP - 554

EP - 565

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 2

ER -