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Anticancer Drugs. 2009 Sep;20(8):682-92. doi: 10.1097/CAD.0b013e32832e14e1.

Gene expression-signature of belinostat in cell lines is specific for histone deacetylase inhibitor treatment, with a corresponding signature in xenografts.

Author information

1
aSTB Laboratory of Functional Genomics, SAIC-Frederick Inc., PO Box B, NCI-Frederick, 1032 Boyles Street, Frederick, MD 21702, USA. monksa@mail.nih.gov

Abstract

Belinostat is a hydroxamate-type histone deactylase inhibitor (HDACi), which has recently entered phase I and II clinical trials. Microarray-based analysis of belinostat-treated cell lines showed an impact on genes associated with the G2/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.

PMID:
19606018
DOI:
10.1097/CAD.0b013e32832e14e1
[Indexed for MEDLINE]

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