Combining histone deacetylase inhibitor vorinostat with aurora kinase inhibitors enhances lymphoma cell killing with repression of c-Myc, hTERT, and microRNA levels

Leo Kretzner, Anna Scuto, Pamela M. Dino, Claudia M. Kowolik, Jun Wu, Patrick Ventura, Richard Jove, Stephen J. Forman, Yun Yen, Mark H. Kirschbaum

研究成果: 雜誌貢獻文章同行評審

85 引文 斯高帕斯(Scopus)

摘要

MK-0457 and MK-5108 are novel aurora kinase inhibitors (AKi) leading to G2-M cell-cycle arrest. Growth and survival of multiple lymphoma cell lines were studied with either drug alone or in combination with vorinostat, a histone deacetylase inhibitor (HDACi), using MTS and Annexin V assays, followed by molecular studies. Either of the AKi alone at 100 to 500 nmol/L resulted in approximately 50% reduced cell growth and 10% to 40% apoptosis. Addition of vorinostat reactivated proapoptotic genes and enhanced lymphoma cell death. Quantitative PCR and immunoblotting revealed that epigenetic and protein acetylation mechanisms were responsible for this activity. The prosurvival genes Bcl-XL and hTERT were downregulated 5-fold by combination drug treatment, whereas the proapoptotic BAD and BID genes were upregulated 3-fold. The p53 tumor suppressor was stabilized by an increased acetylation in response to vorinostat and a reduced Ser315 phosphorylation in response to aurora kinase A. Vorinostat or trichostatin A decreased MYC mRNA and protein as well as c-Myc-regulated microRNAs. MYC is a critical gene in these responses, as MYC knockdown combined with the expression of the c-Myc antagonist MXD1 raised cell sensitivity to the effects of either AKi. Thus, the HDACi vorinostat leads to both transcriptional and posttranscriptional changes to create a proapoptotic milieu, sensitizing cells to mitosisspecific agents such as AKis.

原文英語
頁(從 - 到)3912-3920
頁數9
期刊Cancer Research
71
發行號11
DOIs
出版狀態已發佈 - 六月 1 2011

ASJC Scopus subject areas

  • 腫瘤科
  • 癌症研究

指紋

深入研究「Combining histone deacetylase inhibitor vorinostat with aurora kinase inhibitors enhances lymphoma cell killing with repression of c-Myc, hTERT, and microRNA levels」主題。共同形成了獨特的指紋。

引用此