title: Valproate inhibits colon cancer growth through cell cycle modification in vivo and in vitro.
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.
authors.affiliation: Departments of General and Visceral Surgery, and.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Strey
authors.forename: Lea
authors.initials: L
authors.lastname: Schamell
authors.forename: Elsie
authors.initials: E
authors.lastname: Oppermann
authors.forename: Axel
authors.initials: A
authors.lastname: Haferkamp
authors.forename: Wolf O
authors.initials: WO
authors.lastname: Bechstein
authors.forename: Roman A
authors.initials: RA
authors.lastname: Blaheta