Journal
EUROPEAN JOURNAL OF CANCER
Volume 45, Issue 10, Pages 1846-1854Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2009.03.002
Keywords
Clusterin; Histone deacetylase inhibitor; Drug resistance; Combination therapy
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Funding
- Cure Cancer Australia Foundation
- National Health & Medical Research Council
- Cancer institute New South Wales
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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. (C) 2009 Elsevier Ltd. All rights reserved.
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