title: Over-expression of clusterin is a resistance factor to the anti-cancer effect of histone deacetylase inhibitors.
abstract: 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.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Pei Y
authors.initials: PY
authors.lastname: Liu
authors.forename: Andrew E L
authors.initials: AE
authors.lastname: Tee
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.forename: Murray D
authors.initials: MD
authors.lastname: Norris
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall