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

Leuk Res. 2005 Nov;29(11):1335-42. doi: 10.1016/j.leukres.2005.04.018.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Butyrates / pharmacology
  • Cell Cycle / drug effects
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cyclin D1 / biosynthesis*
  • Cyclin D1 / drug effects
  • Cyclin-Dependent Kinase Inhibitor p27 / biosynthesis*
  • Cyclin-Dependent Kinase Inhibitor p27 / drug effects
  • Cytarabine / pharmacology*
  • Enzyme Inhibitors / pharmacology*
  • Etoposide / pharmacology
  • Histone Deacetylase Inhibitors*
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / metabolism*
  • Valproic Acid / pharmacology*

Substances

  • Butyrates
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Cytarabine
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27
  • Valproic Acid
  • Etoposide