Combination therapy with the histone deacetylase inhibitor LBH589 and radiation is an effective regimen for prostate cancer cells

PLoS One. 2013 Aug 26;8(8):e74253. doi: 10.1371/journal.pone.0074253. eCollection 2013.

Abstract

Radiation therapy (RT) continues to be one of the most popular treatment options for localized prostate cancer (CaP). The purpose of the study was to investigate the in vitro effect of LBH589 alone and in combination with RT on the growth and survival of CaP cell lines and the possible mechanisms of radiosensitization of this combination therapy. The effect of LBH589 alone or in combination with RT on two CaP cell lines (PC-3 and LNCaP) and a normal prostatic epithelial cell line (RWPE-1) was studied by MTT and clonogenic assays, cell cycle analysis, western blotting of apoptosis-related and cell check point proteins, and DNA double strand break (DSB) repair markers. The immunofluorescence staining was used to further confirm DSB expression in treated CaP cells. Our results indicate that LBH589 inhibited proliferation in both CaP and normal prostatic epithelial cells in a time-and-dose-dependent manner; low-dose of LBH589 (IC20) combined with RT greatly improved efficiency of cell killing in CaP cells; compared to RT alone, the combination treatment with LBH589 and RT induced more apoptosis and led to a steady increase of sub-G1 population and abolishment of RT-induced G2/M arrest, increased and persistent DSB, less activation of non-homologous end joining (NHEJ)/homologous recombination (HR) repair pathways and a panel of cell cycle related proteins. These results suggest that LBH589 is a potential agent to increase radiosensitivity of human CaP cells. LBH589 used either alone, or in combination with RT is an attractive strategy for treating human CaP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Cycle / radiation effects
  • Cell Line, Tumor
  • Combined Modality Therapy
  • DNA Damage
  • Flow Cytometry
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Humans
  • Hydroxamic Acids / therapeutic use*
  • Indoles / therapeutic use*
  • Male
  • Panobinostat
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / pathology*
  • Prostatic Neoplasms / radiotherapy
  • Recombination, Genetic

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • Panobinostat

Grant support

This study was in part supported by a Career Development Fellowship from National Health Medical Research Council (YL), Australia; St George Hospital Cancer Research Trust Fund (PHG), Sydney, Australia; and China Scholarship Council (WWX), China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.