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Published on: May 15, 2019

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

Luca Paoluzzi1, Luigi Scotto, Enrica Marchi

  • 1Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|January 14, 2010
PubMed
Abstract

Insights

Histone deacetylase inhibitors (HDACI) like romidepsin and belinostat show promise for mantle cell lymphoma (MCL) treatment. Combining HDACI with bortezomib demonstrated synergistic cytotoxicity and efficacy in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma characterized by cyclin D1 overexpression.
  • Histone deacetylase inhibitors (HDACI) induce cancer cell death and differentiation.
  • HDACI mechanisms include upregulating death receptors and cell cycle arrest.

Purpose of the Study:

  • To investigate the in vitro and in vivo efficacy of romidepsin and belinostat, alone and in combination with bortezomib, in MCL.
  • To explore the synergistic potential of HDACI and proteasome inhibitors in MCL treatment.

Main Methods:

  • Cytotoxicity assays with mathematical synergism analysis.
  • Flow cytometry and immunoblotting for mechanistic studies.
  • Evaluation in a severe combined immunodeficient beige mouse xenograft model.

Main Results:

  • Romidepsin and belinostat exhibited concentration-dependent cytotoxicity against MCL cell lines.
  • HDACI combined with bortezomib showed strong in vitro synergism and induced apoptosis in MCL cells but not in healthy donor cells.
  • Combination therapy decreased cyclin D1 and Bcl-X(L) while increasing acetylated histone H3, acetylated alpha-tubulin, and Noxa.
  • In vivo, belinostat plus bortezomib enhanced efficacy in an MCL xenograft model.

Conclusions:

  • HDACI, such as romidepsin or belinostat, in combination with proteasome inhibitors represent a rational and novel therapeutic strategy for MCL.
  • This combination warrants further clinical investigation for MCL treatment.

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