title: Increase in Ara-C cytotoxicity in the presence of valproate, a histone deacetylase inhibitor, is associated with the concurrent expression of cyclin D1 and p27(Kip 1) in acute myeloblastic leukemia cells.
abstract: The effects of valproate and butyrate were investigated in an acute myeloblastic cell line (OCI/AML-2) on cytotoxicity, cell cycle profile and expression of cell cycle regulating proteins in the presence of cytarabine (Ara-C) and etoposide. As a single agent valproate and butyrate inhibited AML cell growth but did not significantly induce cell death. A dramatic increase in cytotoxicity was observed when combining valproate or butyrate with Ara-C, whereas, co-addition of them with etoposide had much smaller effect on cell death. Valproate induced a clear G1 phase arrest and up-regulated cyclin D1 expression in the presence of Ara-C and etoposide. In addition, valporate was able to block the Ara-C-induced down-regulation of p27(Kip1) expression but not that induced by etoposide.
authors.affiliation: Department of Internal Medicine, University of Oulu, PL 20, OYS 90029, Finland. timo.siitonen@ppshp.fi
authors.forename: Timo
authors.initials: T
authors.lastname: Siitonen
authors.forename: Pirjo
authors.initials: P
authors.lastname: Koistinen
authors.forename: Eeva-Riitta
authors.initials: ER
authors.lastname: Savolainen
mesh_terms: D002087:Butyrates / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis* / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D002087:Butyrates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D003561:Cytarabine; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014635:Valproic Acid; D005047:Etoposide