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

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 microM. 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.

• Authors: Alison V Fraser, Patrick M Woster, Heather M Wallace
• Journal: The Biochemical journal (Biochem J) Vol. 367 Issue Pt 1 Pg. 307-12 (Oct 01 2002) ISSN: 0264-6021 [Print] England
• PMID: 12086584 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites
• N(1)-ethyl-N-(11)-(2-methyl-1-butyl)-4,8-diazaundecane
• Nucleic Acid Synthesis Inhibitors
• Polyamines
• Etoposide
• Acetyltransferases
• diamine N-acetyltransferase
• Caspases

Topics

• Acetyltransferases (metabolism)
• Antimetabolites (pharmacology)
• Apoptosis
• Caspases (metabolism)
• Dose-Response Relationship, Drug
• Etoposide (pharmacology)
• HL-60 Cells
• Humans
• Leukemia (pathology)
• Nucleic Acid Synthesis Inhibitors (pharmacology)
• Polyamines (metabolism, pharmacology)
• Time Factors
• Tumor Cells, Cultured