Liu Tao, Liu Pei Y, Tee Andrew E L, Haber Michelle, Norris Murray D, Gleave Martin E, Marshall Glenn M
Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, NSW, Australia.
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.
组蛋白去乙酰化酶抑制剂（HDACIs）可调节基因转录，是最有前景的新型抗癌药物类别之一。OGX-011是一种靶向聚集素的反义寡核苷酸，可使癌细胞对化疗和放疗敏感。通过回顾文献中报道的微阵列基因谱数据，我们确定聚集素是大多数HDACIs在不同器官来源的癌细胞系中共同上调的仅有的两个基因之一。在HDACI耐药癌细胞中，抑制聚集素基因表达通过细胞色素C介导的线粒体凋亡协同增强高剂量HDACI诱导的细胞死亡，并且在HDACI敏感和HDACI耐药肿瘤细胞中协同增强低剂量HDACI诱导的生长停滞，但在正常细胞中则不然。在接种神经母细胞瘤细胞的小鼠中，OGX-011与HDACI丙戊酸盐联合使用可协同抑制肿瘤生长。我们的数据表明，HDACI诱导的聚集素过表达使癌细胞对HDACI诱导的生长停滞和凋亡产生抗性，并建议在未来癌症患者的临床试验中将OGX-011添加到HDACIs中。
