Valproate inhibits colon cancer growth through cell cycle modification in vivo and in vitro

Strey,Christoph  W.; Schamell,Lea; Oppermann,Elsie; Haferkamp,Axel; Bechstein,Wolf  O.; Blaheta,Roman  A.

doi:10.3892/etm.2011.202

Valproate inhibits colon cancer growth through cell cycle modification in vivo and in vitro

Authors:
- Christoph W. Strey
- Lea Schamell
- Elsie Oppermann
- Axel Haferkamp
- Wolf O. Bechstein
- Roman A. Blaheta
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Affiliations: Department of General and Visceral Surgery, Johann Wolfgang Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany, Department of Urology, Johann Wolfgang Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany
Published online on: January 20, 2011 https://doi.org/10.3892/etm.2011.202
Pages: 301-307

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Abstract

Valproate (VPA) is a well-characterized histone deacetylase inhibitor with anti-neoplastic properties. We analyzed the growth blocking effects and the molecular mode of action of this compound in colorectal cancer cells in vitro and in vivo. Caco-2, SW-480, CX-1 or WIDR cell lines were exposed to VPA (0.25-2 mM) for various time periods. Cell growth, cell cycle progression and apoptosis were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide dye reduction assay and flow cytometry. Cell cycle- and apoptosis-regulating proteins and histone acetylation were assessed by Western blotting. In vivo tumor growth and regulating protein expression under VPA were investigated in a subcutaneous xenograft tumor model. VPA inhibited the growth of all cell lines with cell cycle arrest paralleled by the up-regulation of H3 and H4 acetylation. In vivo tumor growth was substantially depressed by VPA (200 mg/kg bw). Cell cycle proteins (cdk1, cdk2, cdk4, cyclin D, cyclin E, p19, p21 and p27) were differentially altered by VPA. Predominantly cdk1 was decreased and p27 was up-regulated in all models. Apoptosis-related proteins were altered in vivo with up-regulation of bax and down-regulation of bcl-2. VPA exerts anti-neoplastic activity in colorectal tumor cell lines in vitro and in vivo by altering cell cycle regulation.

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