Suberoylanilide hydroxamic acid combined with gemcitabine enhances apoptosis in non-small cell lung cancer. Academic Article uri icon

Overview

abstract

  • BACKGROUND: We have shown that non-small cell lung cancer (NSCLC) is resistant to the histone deacetylase inhibitor (HDI) suberoylanilide hydroxamic acid (SAHA) through upregulation of the antiapoptotic transcription factor nuclear factor-kappaB (NF-kappaB). HDIs also promote chromatin remodeling, potentially making the DNA more accessible to chemotherapy. We hypothesize that combined SAHA and gemcitabine sensitizes NSCLC to apoptosis. METHODS: Three NSCLC cell lines (A549, H358, H460) were untreated, or treated with SAHA, gemcitabine, or both agents. NF-kappaB-dependent transcription was determined by reporter gene assays, reverse transcriptase-polymerase chain reaction RT-PCR, and Western blot analysis for the NF-kappaB-regulated antiapoptotic gene MnSOD. Survival of NSCLC cells overexpressing Bfl/A1, Bcl-X(L), or MnSOD and treated with SAHA and gemcitabine was determined in the presence or absence of NF-kappaB. Survival of treated cells overexpressing HDAC-1, 2, 3 or p/CAF was determined. Apoptosis was determined by fluorescence-activated cell sorter analysis, DNA fragmentation, and caspase-3 activity. Colony formation assays were performed on cells treated concurrently and sequentially with SAHA and gemcitabine. Assays were performed in triplicate, and the Student t test was applied as appropriate. RESULTS: SAHA-activated NF-kappaB (P

publication date

  • August 1, 2005

Research

keywords

  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Carcinoma, Non-Small-Cell Lung
  • Deoxycytidine
  • Hydroxamic Acids
  • Lung Neoplasms

Identity

Scopus Document Identifier

  • 24344498688

Digital Object Identifier (DOI)

  • 10.1016/j.surg.2005.06.016

PubMed ID

  • 16153448

Additional Document Info

volume

  • 138

issue

  • 2