The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1

Roberto R. Rosato, Jorge A. Almenara, Steven Grant

Research output: Contribution to journalArticle

410 Scopus citations

Abstract

Effects of the histone deacetylase (HDAC) inhibitor MS-275 have been examined in human leukemia and lymphoma cells (U937, HL-60, K562, and Jurkat) as well as in primary acute myelogenous leukemia blasts in relation to differentiation and apoptosis. MS-275 displayed dose-dependent effects in each of the cell lines. When administered at a low concentration (e.g., 1 μM), MS-275 exhibited potent antiproliferative activity, inducing p21CIP1/WAF1-mediated growth arrest and expression of differentiation markers (CD11b) in U937 cells. These events were accompanied by an increase in hypophosphorylated retinoblastoma protein and down-regulation of cell cycle-related proteins including cylin D1. However, at higher concentrations (e.g., 5 μM), MS-275 potently induced cell death, triggering apoptosis in ∼70% of cells at 48 h. In contrast to other HDAC inhibitors such as apicidin, the extrinsic, receptor-mediated pathway played a minimal role in MS-275 lethality. However, MS-275 potently induced a very early (e.g., within 2 h) increase in reactive oxygen species (ROS), followed by the loss of mitochondrial membrane potential (Δψm) and cytosolic release of cytochrome c. These events culminated in activation of the caspase cascade, manifested by poly(ADP-ribose) polymerase, p21CIP1/WAF1, p27KIP, Bcl-2, and retinoblastoma protein degradation. MS275 exposure also resulted in diminished expression of cyclin DI and the antiapoptotic proteins Mcl-1 and XIAP. Administration of the free radical scavenger L-N-acetylcysteine blocked MS-275-mediated mitochondrial injury and apoptosis, suggesting a primary role for ROS generation in MS-275-associated lethality. Lastly, U937 cells stably expressing a p21CIP1/WAF1, antisense construct were significantly more sensitive to MS-275-mediated apoptosis than controls, but they were impaired in their differentiation response. Together, these findings demonstrate that MS-275 exerts dose-dependent effects in human leukemia cells, i.e., p21CIP1/WAF1-dependent growth arrest and differentiation at low drug concentrations and a marked induction of ROS, mitochondrial damage, caspase activation, and apoptosis at higher concentrations.

Original languageEnglish (US)
Pages (from-to)3637-3645
Number of pages9
JournalCancer research
Volume63
Issue number13
StatePublished - Jul 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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