Induction of HL-60 cell differentiation by the p38 mitogen-activated protein kinase inhibitor SB203580 is mediated through the extracellular signal-regulated kinase signaling pathway

Jin Xia Zhang, Wie Jian Zhuang, Ka Hung Poon, Michael Yang, David W F FONG*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

The pyridinyl imidazole p38 kinase inhibitor, SB203580, was initially used to block inflammatory cytokine synthesis. Here we report that SB203580 by itself could induce human promyeloid leukemic HL-60 cells to differentiate mainly along the granulocytic lineage, as evidenced by cellular morphological changes, and the concurrent expression of cell surface markers CD11b and CD14. This differentiation induction was time and dose dependent. After 12 h exposure to 10 μM SB203580, 12.5% of the cells became CD11b+ as compared to only 2.6% in untreated control cells. By 96 h, CD11b+ cells increased to 72.3%, and among them, 26% were CD14+. Morphologically, the cells were smaller in size with lower nuclear/cytoplasmic ratio. The nucleus was indented and nucleoli markedly reduced. However, 10 μM SB203580 had little effect on HL-60 cell growth and survival during the first 72 h, but by 96 h the percentage of cells in G1 phase was markedly increased. These effects of SB203580 were not attributable to its inhibition of p38 kinase activity. Instead, the essential kinases in the extracellular signal-regulated kinase (ERK) pathway such as phospho-Raf-1, phospho-MEK1/2, phospho-ERK1/2 and phospho-p90RSK were all elevated dramatically shortly after cells were exposed to SB203580 and lasted for 24 h before declining. Preincubation of cells with 20 μM of PD98059 1 h before addition of SB203580 could completely block the expression of differentiation markers. Our results suggest that SB203580-induced differentiation in HL-60 cells was mediated by activation of MEK/ERK signaling. In conclusion, our data have shown that SB203580 possessed biological activities other than inhibition of p38 and these activities could make it a potential candidate as an inducing agent for cell differentiation in the therapeutic treatment of leukemia.

Original languageEnglish
Pages (from-to)31-38
Number of pages8
JournalAnti-Cancer Drugs
Volume14
Issue number1
DOIs
Publication statusPublished - Jan 2003

Scopus Subject Areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

User-Defined Keywords

  • Differentiation
  • HL-60
  • Mitogen-activated protein kinase
  • p38 kinase
  • p38 kinase inhibitor
  • SB203580

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