Abstract
Introduction
Vorinostat is a small molecule inhibitor of class I and II histone deacetylase enzymes which alters the expression of target genes including the cell cycle gene p21, leading to cell cycle arrest and apoptosis.
Methods
Patients enrolled in a phase I trial were treated with vorinostat alone on day 1 and vorinostat and bortezomib in combination on day 9. Paired biopsies were obtained in eleven subjects. Blood samples were obtained on days 1 and 9 of cycle 1 prior to dosing and 2 and 6 h post-dosing in all 60 subjects. Gene expression of p21, HSP70, AKT, Nur77, ERB1, and ERB2 was evaluated in peripheral blood mononuclear cells and tissue samples. Chromatin immunoprecipitation of p21, HSP70, and Nur77 was also performed in biopsy samples.
Results
In peripheral blood mononuclear cells, Nur77 was significantly and consistently decreased 2 h after vorinostat administration on both days 1 and 9, median ratio of gene expression relative to baseline of 0.69 with interquartile range 0.49–1.04 (p < 0.001); 0.28 (0.15–0.7) (p < 0.001), respectively, with more pronounced decrease on day 9, when patients received both vorinostat and bortezomib. p21, a downstream target of Nur77, was significantly decreased on day 9, 2 and 6 h after administration of vorinostat and bortezomib, 0.67 (0.41–1.03) (p < 0.01); 0.44 (0.25–1.3) (p < 0.01), respectively. The ChIP assay demonstrated a protein–DNA interaction, in this case interaction of Nur77, HSP70 and p21 with acetylated histone H3, at baseline and at day 9 after treatment with vorinostat in tissue biopsies in most patients.
Conclusion
Vorinostat inhibits Nur77 expression, which in turn may decrease p21 and AKT expression in PBMCs. The influence of vorinostat on target gene expression in tumor tissue was variable; however, most patients demonstrated interaction of acetylated H3 with Nur77, HSP70, and p21 which provides evidence of interaction with the transcriptionally active acetylated H3.
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Acknowledgments
We thank the University of Wisconsin Carbone Cancer Center (UWCCC) Analytical Instrumentation Laboratory for Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics (3P Lab) for acquisition of gene expression and chromatin precipitation data for this research. We also thank the patients who participated in this clinical trial, and the nurses and research specialist of the UWCCC Phase I Program for their efforts in conducting and managing this trial. UO1 CA062491, Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis, NCI; CTEP Translational Research Initiative, Contract; and 1UL 1RR025011, Clinical and Translational Science Award, National Center for Research Resources, NIH. The authors would like to thank the University of Wisconsin Carbone Cancer Center (UWCCC) for use of its Shared Services to complete this research. This work is supported in part by NIH/NCI P30 CA014520 to the UW Carbone Cancer Center.
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Kolesar, J.M., Traynor, A.M., Holen, K.D. et al. Vorinostat in combination with bortezomib in patients with advanced malignancies directly alters transcription of target genes. Cancer Chemother Pharmacol 72, 661–667 (2013). https://doi.org/10.1007/s00280-013-2242-6
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DOI: https://doi.org/10.1007/s00280-013-2242-6