Journal
ANTI-CANCER DRUGS
Volume 20, Issue 8, Pages 682-692Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CAD.0b013e32832e14e1
Keywords
belinostat; gene signature; histone deacetylase inhibitor
Categories
Funding
- National Cancer Institute
- National Institutes of Health [N01-CO-12400]
Ask authors/readers for more resources
Belinostat is a hydroxamate-type histone deactylase inhibitor (HDACi), which has recently entered phase I and 11 clinical trials. Microarray-based analysis of belinostat-treated cell lines showed an impact on genes associated with the G(2)/M phase of the cell cycle and downregulation of the aurora kinase pathway. Expression of 25 dysregulated genes was measured in eight differentially sensitive cell lines using a novel high-throughput assay that combines multiplex reverse transcriptase-PCR and fluorescence capillary electrophoresis. Sensitivity to belinostat and the magnitude of changes in overall gene modulation were significantly correlated. A belinostat-gene profile was specific for HDACi in three cell lines when compared with equipotent concentrations of four mechanistically different chemotherapeutic agents: 5-fluorouracil, cisplatin, paclitaxel, and thiotepa. Belinostat- and trichostatin A (HDACi)-induced gene responses were highly correlated with each other, but not with the limited changes in response to the other non-HDACi agents. Moreover, belinostat treatment of mice bearing human xenografts showed that the preponderance of selected genes were also modulated in vivo, more extensively in a drug-sensitive tumor than a more resistant model. We have demonstrated a gene signature that is selectively regulated by HDACi when compared with other clinical agents allowing us to distinguish HDACi responses from those related to other mechanisms. Anti-Cancer Drugs 20:682-692 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available