Over-expression of clusterin is a resistance factor to the anti-cancer effect of histone deacetylase inhibitors

Eur J Cancer. 2009 Jul;45(10):1846-54. doi: 10.1016/j.ejca.2009.03.002. Epub 2009 Apr 1.


Histone deacetylase inhibitors (HDACIs) modulate gene transcription and are among the most promising new classes of anticancer drugs. OGX-011, an anti-sense oligonucleotide targeting clusterin, sensitises cancer cells to chemo- and radiotherapies. By reviewing microarray gene profiling data reported in the literature, we identified clusterin as one of only two genes commonly up-regulated by most HDACIs in cancer cell lines of different organ origins. Suppression of clusterin gene expression synergistically enhanced high-dosage HDACI-induced cell death through cytochrome C-mediated mitochondrial apoptosis in HDACI-resistant cancer cells, and synergistically enhanced low-dosage HDACI-induced growth arrest in both HDACI-sensitive and HDACI-resistant tumour cells, but not in normal cells. In mice xenografted with neuroblastoma cells, combination of OGX-011 and the HDACI, valproate, synergistically repressed tumour growth. Our data indicate that HDACI-induced clusterin over-expression renders cancer cells resistant to HDACI-induced growth arrest and apoptosis, and suggests the addition of OGX-011 to HDACIs in future clinical trials in cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects
  • Clusterin / genetics
  • Clusterin / metabolism*
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histone Deacetylase Inhibitors*
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Oligonucleotides, Antisense / pharmacology
  • Thionucleotides / pharmacology
  • Tumor Cells, Cultured
  • Up-Regulation / drug effects
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Clusterin
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Neoplasm Proteins
  • OGX-011
  • Oligonucleotides, Antisense
  • Thionucleotides