title: [Synergistic cytotoxicity effect of histone deacetylase inhibitor combined with paclitaxel on lung cancer cell lines and its mechanism].
abstract: OBJECTIVE
  Histone deacetylase (HDAC) inhibitors can inhibit cell signal network function through decreasing expression of multiple genes and proteins, thus affect cell proliferation, survival and chemosensitivity. HDAC inhibitors combined with paclitaxel may enhance the inhibitory effect of drugs on lung cancer cells. This study was to observe the synergistic anti-proliferative effect of HDAC inhibitor trichostatin A (TSA) combined with paclitaxel on lung cancer cell lines H322 and H1299, and to investigate its mechanism.
  
  
  METHODS
  H322 and H1299 cells were divided into control group, paclitaxel (TAX) group, TSA group, and combination group (TF group, TSA followed by paclitaxel). Cell proliferation was determined by MTT assay. Cell cycle and apoptosis were determined by flow cytometry. The protein expression levels of survivin, ERK, and PARP were determined by Western blot analysis.
  
  
  RESULTS
  When combined with TSA, the 50% inhibition concentration (IC50) of paclitaxel decreased from (48.07+/-26.12) nmol/L to (6.34+/-5.72) nmol/L in H322 cells and from (110.6+/-38.7) nmol/L to (63.7+/-11.8) nmol/L in H1299 cells, with significant differences (P<0.05). Apoptosis rate of H322 cells was higher in the the TF group than in the TAX group(P<0.05). There were more necrosis cells in the TF group of H1299 cell line than in the other groups. pERK was up-regulated in the TAX group of H322 cell line. Expression of Survivin was up-regulated in the TAX group of two cells. Expressions of Survivin and pERK were down-regulated in the TSA and TF groups of two cell lines. Cleaved PARP was detected in the TAX and the TF groups of H322 cells, and its expression was significantly higher in the the TF group than in the TAX group. Cleaved PARP was not detected in each group of H1299 cells.
  
  
  CONCLUSIONS
  TSA combined with paclitaxel has a synergistic cytotoxicity effect on lung cancer cell lines H322 and H1299 when the cells were treated with TSA followed by paclitaxel. The mechanism may be that TSA down-regulates the survivin high-expression induced by paclitaxel, and blocks pERK protein expression.
authors: Geriatric Respiratory Department,PLA General Hospital, Beijing 100853,P. R. China. zhangd1117@yahoo.com
authors: Dong
authors: D
authors: Zhang
authors: Chang-Ting
authors: CT
authors: Liu
authors: Xiao-Dan
authors: XD
authors: Yu
authors: Yan
authors: Y
authors: Liu
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000077022:Survivin
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; C012589:trichostatin A; D011065:Poly(ADP-ribose) Polymerases; D048049:Extracellular Signal-Regulated MAP Kinases; D017239:Paclitaxel