Vorinostat in combination with bortezomib in patients with advanced malignancies directly alters transcription of target genes

Jill M. Kolesar; Anne M. Traynor; Kyle D. Holen; Tien Hoang; Songwon Seo; KyungMann Kim; Dona Alberti; Igor Espinoza-Delgado; John J. Wright; George Wilding; Howard H. Bailey; William R. Schelman

doi:10.1007/s00280-013-2242-6

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Vorinostat in combination with bortezomib in patients with advanced malignancies directly alters transcription of target genes

Journal article

Peer reviewed

Vorinostat in combination with bortezomib in patients with advanced malignancies directly alters transcription of target genes

Jill M. Kolesar, Anne M. Traynor, Kyle D. Holen, Tien Hoang, Songwon Seo, KyungMann Kim, Dona Alberti, Igor Espinoza-Delgado, John J. Wright, George Wilding, …

Cancer chemotherapy and pharmacology, Vol.72(3), pp.661-667

09/01/2013

DOI: 10.1007/s00280-013-2242-6

PMCID: PMC3926898

PMID: 23903894

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https://www.ncbi.nlm.nih.gov/pmc/articles/3926898View

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Abstract

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. 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. 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. 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.

Life Sciences & Biomedicine

Oncology

Pharmacology & Pharmacy

Science & Technology

Details

Title: Subtitle: Vorinostat in combination with bortezomib in patients with advanced malignancies directly alters transcription of target genes
Creators: Jill M. Kolesar - University of Wisconsin Carbone Cancer Center
Anne M. Traynor - University of Wisconsin Carbone Cancer Center
Kyle D. Holen - University of Wisconsin Carbone Cancer Center
Tien Hoang - University of Wisconsin Carbone Cancer Center
Songwon Seo - University of Wisconsin Carbone Cancer Center
KyungMann Kim - University of Wisconsin Carbone Cancer Center
Dona Alberti - University of Wisconsin Carbone Cancer Center
Igor Espinoza-Delgado - NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA
John J. Wright - NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA
George Wilding - University of Wisconsin Carbone Cancer Center
Howard H. Bailey - University of Wisconsin Carbone Cancer Center
William R. Schelman - University of Wisconsin Carbone Cancer Center
Resource Type: Journal article
Publication Details: Cancer chemotherapy and pharmacology, Vol.72(3), pp.661-667
DOI: 10.1007/s00280-013-2242-6
PMID: 23903894
PMCID: PMC3926898
NLM abbreviation: Cancer Chemother Pharmacol
ISSN: 0344-5704
eISSN: 1432-0843
Publisher: Springer Nature
Number of pages: 7
Grant note: P30 CA014520 / NIH/NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) UL1RR025011 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) P30CA014520 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) UL1TR000427 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) 1UL 1RR025011 / Clinical and Translational Science Award, National Center for Research Resources, NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA UO1 CA062491 / Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis, NCI; CTEP Translational Research Initiative
Language: English
Date published: 09/01/2013
Academic Unit: Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
Record Identifier: 9984696546902771

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