title: Vorinostat modulates cell cycle regulatory proteins in glioma cells and human glioma slice cultures.
abstract: Chromatin modification through histone deacetylase inhibition has shown evidence of activity against malignancies. The mechanism of action of such agents are pleiotropic and potentially tumor specific. In this study, we studied the mechanisms of vorinostat-induced cellular effects in gliomas. The effects of vorinostat on proliferation, induction of apoptosis and cell cycle effects were studied in vitro (D54, U87 and U373 glioma cell lines). To gain additional insights into its effects on human gliomas, vorinostat-induced changes were examined ex vivo using a novel organotypic human glioma slice model. Vorinostat treatment resulted in increased p21 levels in all glioma cells tested in a p53 independent manner. In addition, cyclin B1 levels were transcriptionally downregulated and resulted in reduced kinase activity of the cyclin B1/cdk1 complex causing a G2 arrest. These effects were associated with a dose- and time-dependent inhibition of cellular proliferation and anchorage-independent growth in association with hyperacetylation of core histones and induction of apoptosis. Of particular significance, we demonstrate histone hyperacetylation and increased p21 levels in freshly resected human glioma specimens maintained as organotypic slice cultures and exposed to vorinostat similar to cell lines suggesting that human glioma can be targeted by this agent. Our data suggest that the effects of vorinostat are associated with modulation of cell cycle related proteins and activation of a G2 checkpoint along with induction of apoptosis. These effects are mediated by both transcriptional and post-translational mechanisms which provide potential options that can be exploited to develop new therapeutic approaches against gliomas.
authors: Department of Neuro-Oncology, The Brain Tumor Center, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX 77030, USA.
authors: Jihong
authors: J
authors: Xu
authors: Deepa
authors: D
authors: Sampath
authors: Frederick F
authors: FF
authors: Lang
authors: Sujit
authors: S
authors: Prabhu
authors: Ganesh
authors: G
authors: Rao
authors: Gregory N
authors: GN
authors: Fuller
authors: Yuanfang
authors: Y
authors: Liu
authors: Vinay K
authors: VK
authors: Puduvalli
references: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2041-6
references: 12576549
references: Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3003-7
references: 9501205
references: J Neurochem. 2005 May;93(4):992-9
references: 15857402
references: Apoptosis. 2007 Jul;12(7):1327-38
references: 17351739
references: Cell. 2007 Feb 23;128(4):683-92
references: 17320506
references: Clin Cancer Res. 2005 Feb 15;11(4):1539-44
references: 15746058
references: J Neurooncol. 2007 Jul;83(3):267-75
references: 17310267
references: Clin Cancer Res. 2007 Feb 1;13(3):1045-52
references: 17289901
references: Expert Rev Anticancer Ther. 2007 May;7(5):641-61
references: 17492929
references: Cancer Res. 2005 May 1;65(9):3617-23
references: 15867356
references: Apoptosis. 2005 Jan;10(1):233-43
references: 15711939
references: Clin Cancer Res. 2007 Jan 1;13(1):18-26
references: 17200334
references: Curr Opin Cell Biol. 2000 Dec;12(6):658-65
references: 11063929
references: Brain Tumor Pathol. 2001;18(2):109-14
references: 11908866
references: Nat Clin Pract Oncol. 2005 Dec;2 Suppl 1:S4-11
references: 16341240
references: Neurosci Res. 2006 Dec;56(4):450-8
references: 17049657
references: Ai Zheng. 2002 Oct;21(10):1100-5
references: 12508652
references: Mol Cancer Ther. 2007 Feb;6(2):692-702
references: 17308065
references: J Clin Oncol. 2009 Apr 20;27(12):2052-8
references: 19307505
references: Acta Neuropathol. 2005 Aug;110(2):178-84
references: 16025287
references: Biochemistry. 2000 Aug 8;39(31):9494-501
references: 10924145
references: Nat Rev Genet. 2001 Feb;2(2):120-9
references: 11253051