Induction of apoptosis in human leukaemic cells by IPENSpm, a novel polyamine analogue and anti-metabolite.
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.
Fraser
Alison V
AV
Departments of Medicine & Therapeutics and Biomedical Sciences, Polwarth Building, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, U.K.
Woster
Patrick M
PM
Wallace
Heather M
HM
D000123:Acetyltransferases / Q000378:metabolism; D000963:Antimetabolites / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011073:Polyamines / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D000963:Antimetabolites; D020169:Caspases; D005047:Etoposide; D019384:Nucleic Acid Synthesis Inhibitors; D011073:Polyamines; D000099228:Diamine N-Acetyltransferase; C118772:N(1)-ethyl-N-(11)-(2-methyl-1-butyl)-4,8-diazaundecane