The histone deacetylase inhibitor LBH589 (panobinostat) modulates the crosstalk of lymphocytes with Hodgkin lymphoma cell lines

PLoS One. 2013 Nov 21;8(11):e79502. doi: 10.1371/journal.pone.0079502. eCollection 2013.

Abstract

Epigenetic changes have been implicated in the malignant phenotype of Hodgkin Reed Sternberg (HRS) cells in Hodgkin lymphoma (HL), where HRS survival and proliferation depends on the microenvironment. The histone-deacetylase (HDAC) inhibitor LBH589 (panobinostat) showed clinical efficacy but its impact on the HRS microenvironment is unclear. Hence, we analysed the effects of LBH589 on lymphocytes and also potential combination therapies. In lymphocyte-target cell killing assays, LBH589-treatment triggered an enhanced lymphocyte-dependent lysis of HL cells despite of mild lymphocytopenic effects. In co-culture experiments of lymphocytes with HL cells, LBH589 suppressed the IFNgamma-release but increased the TNFalpha secretion. Recombinant TNFalpha boosted the lymphocyte-dependent lysis of HL target cells. In HL cell lines, LBH589 induced cell death, autophagy, and an increase of MICA/B that are ligands to natural killer cell receptors. The combination of LBH589 with Brentuximab Vedotin was inefficient due to down-regulation of CD30 as a target. Combination with gemcitabine revealed highly significant effects, suggesting a potential combination for future therapy. Based on these data we suggest that LBH589 favourably modulates the cytokine network and lymphocyte activity in the HL microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Blotting, Western
  • Brentuximab Vedotin
  • Cell Line, Tumor
  • Cells, Cultured
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Hodgkin Disease / metabolism*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Immunoconjugates / pharmacology
  • Indoles / pharmacology*
  • Interferon-gamma / metabolism
  • Ki-1 Antigen / metabolism
  • Lymphocytes / drug effects*
  • Lymphocytes / metabolism*
  • Microscopy, Fluorescence
  • Panobinostat
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Immunoconjugates
  • Indoles
  • Ki-1 Antigen
  • Tumor Necrosis Factor-alpha
  • Deoxycytidine
  • Brentuximab Vedotin
  • Interferon-gamma
  • Panobinostat
  • gemcitabine

Grant support

The authors thank the Deutsche Forschungsgemeinschaft (DFG) for support (grant 2432/5-1 to HPH and EPvS). We thank Novartis for providing LBH589 and for supporting this project. The funders had no role in study design, data collection and data analysis, decision to publish, or preparation of the manuscript.