Induction of apoptosis in human leukaemic cells by IPENSpm, a novel polyamine analogue and anti-metabolite

Alison Fraser, P. M. Woster, Heather Mann Wallace

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Abstract

Human promyelogenous leukaemic cells (HL-60) were treated with novel spermine analogue, (S)-N-1-(2-methyl-1-butyl)-N-11-ethyl-4,8-diazaundecane (IPENSpm), and the effects on growth and intracellular polyamine metabolism were measured. IPENSpm was cytotoxic to these cells at concentrations greater than 2.5 muM. It induced apoptosis in a caspase-dependent manner and its toxicity profile was comparable with etoposide, a well-known anti-tumour agent and inducer of apoptosis. IPENSpm decreased intracellular polyamine content as a result of changes in ornithine decarboxylase activity and increases in spermidine/ spermine N-1-acetyltransferase and polyamine export. Analysis showed spermine and spermidine as the major intracellular polyamines, while putrescine and acetyl-polyamines were the main export compounds. IPENSpm used the polyamine transporter system for uptake and its accumulation in cells was prevented by polyamine transport inhibitors. IPENSpm can be classified as a polyamine anti-metabolite and it may be a promising new lead compound in terms of treatment of some human cancers.

Original languageEnglish
Pages (from-to)307-312
Number of pages5
JournalBiochemical Journal
Volume367
Issue numberPt 1
DOIs
Publication statusPublished - 2002

Keywords

  • caspase
  • etoposide
  • spermine
  • transport
  • HUMAN CANCER-CELLS
  • ORNITHINE DECARBOXYLASE
  • BREAST-CANCER
  • C-MYC
  • DEATH
  • GROWTH
  • CATABOLISM
  • EFFLUX
  • BIOSYNTHESIS
  • ACETYLATION

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