Combined histone deacetylase and NF-kappaB inhibition sensitizes non-small cell lung cancer to cell death. Academic Article uri icon

Overview

abstract

  • BACKGROUND: Non-small cell lung cancer (NSCLC) remains resistant to traditional and novel chemotherapeutic agents, relating, in part, to the activation of the antiapoptotic transcription factor NF-kappaB. We hypothesize that inhibition of NF-kappaB using BAY-11-7085 will sensitize NSCLC cells to death, induced by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). METHODS: Five tumorigenic NSCLC cell lines (A549, H157, H358, H460, H1299) were treated with nothing, SAHA, BAY-11-7085, or both compounds. Cell death was determined by crystal violet staining. p65 nuclear translocation was determined by Western blot analysis. NF-kappaB activity was determined by reporter-gene assays and by reverse transcriptase-polymerase chain reaction of the endogenous NF-kappaB-dependent gene interleukin 8. Apoptosis was determined by DNA fragmentation. Clonogenic cell survival assays were also performed. Data was analyzed with the Student t test when appropriate. RESULTS: SAHA alone resulted in no meaningful NSCLC cell death. SAHA induced nuclear translocation of p65, which was inhibited by BAY-11-7085. SAHA significantly induced NF-kappaB-dependent transcription which was ameliorated after treatment with BAY-11-7085 (P = .01). Combined SAHA and BAY-11-7085 induced significantly more apoptosis and cell death than either drug alone (P = .002). CONCLUSIONS: Combined HDI and NF-kappaB inhibition using BAY-11-7085 sensitizes NSCLC cells to cell death and appears promising as a novel treatment strategy for this disease.

publication date

  • August 1, 2004

Research

keywords

  • Apoptosis
  • Carcinoma, Non-Small-Cell Lung
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Lung Neoplasms
  • NF-kappa B

Identity

Scopus Document Identifier

  • 3843103805

Digital Object Identifier (DOI)

  • 10.1016/j.surg.2004.05.018

PubMed ID

  • 15300209

Additional Document Info

volume

  • 136

issue

  • 2