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  • Title: Over-expression of clusterin is a resistance factor to the anti-cancer effect of histone deacetylase inhibitors.
    Author: Liu T, Liu PY, Tee AE, Haber M, Norris MD, Gleave ME, Marshall GM.
    Journal: Eur J Cancer; 2009 Jul; 45(10):1846-54. PubMed ID: 19342222.
    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.
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