Gene expression-signature of belinostat in cell lines is specific for histone deacetylase inhibitor treatment, with a corresponding signature in xenografts.
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.
Monks
Anne
A
aSTB Laboratory of Functional Genomics, SAIC-Frederick Inc., PO Box B, NCI-Frederick, 1032 Boyles Street, Frederick, MD 21702, USA. monksa@mail.nih.gov
Hose
Curtis D
CD
Pezzoli
Patrick
P
Kondapaka
Sudhir
S
Vansant
Gordon
G
Petersen
Kamille Dumong
KD
Sehested
Maxwell
M
Monforte
Joseph
J
Shoemaker
Robert H
RH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D064127:Aurora Kinases; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013449:Sulfonamides; D015854:Up-Regulation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D020931:ran GTP-Binding Protein / Q000235:genetics
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004791:Enzyme Inhibitors; D020662:Guanine Nucleotide Exchange Factors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C120587:RAN protein, human; C477650:RCC2 protein, human; D013449:Sulfonamides; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D020931:ran GTP-Binding Protein; C487081:belinostat