Novel dichlorophenyl urea compounds inhibit proliferation of human leukemia HL-60 cells by inducing cell cycle arrest, differentiation and apoptosis

James L. Figarola, Yehua Weng, Christopher Lincoln, David Horne, Samuel Rahbar

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Two novel dichlorophenyl urea compounds, SR4 and SR9, were synthesized in our laboratory and evaluated for anti-cancer activities. Specifically, we investigated the antiproliferative properties of these new compounds on promyelocytic HL-60 leukemia cells by analyzing their effects on cell differentiation, cell cycle progression and apoptosis. SR4 and SR9 were both cytototoxic to HL-60 cells in a dose-and time-dependent manner, with IC50 of 1.2 μM and 2.2 μM, respectively, after 72 h treatment. Both compounds strongly suppressed growth of HL-60 cells by promoting cell cycle arrest at the G0/G1 transition, with concomitant decrease in protein levels of cyclins D1 and E2 and cyclin-dependent kinases (CDK 2 and CDK 4), and increased protein expression of CDK inhibitors p21WAF1/Cip1 and p27Kip1. In addition, either compounds induce cell differentiation as detected by increased NBT staining and expression of CD11b and CD14. Treatment with SR compounds also promoted mitochondrial-dependent apoptosis as confirmed by Annexin V-FITC double staining, DNA fragmentation, increased expression of caspase 3, 7 and 9, cytochrome c release, PARP degradation, and collapse in mitochondrial membrane potential (ΔYMT). Collectively, these results provide evidence that SR4 and SR9 have the potential for the treatment of human leukemia and merit further investigation as therapeutic agents against other types of cancer.

Original languageEnglish (US)
Pages (from-to)1413-1425
Number of pages13
JournalInvestigational New Drugs
Volume30
Issue number4
DOIs
StatePublished - Aug 2012

Keywords

  • Apoptosis
  • Cell cycle arrest
  • Dichlorophenyl urea
  • HL-60
  • Leukemia

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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