Section 41
Chapter 40,626

Major increases in spermidine/spermine-N1-acetyltransferase activity by spermine analogues and their relationship to polyamine depletion and growth inhibition in L1210 cells

Libby, P.R.; Henderson, M.; Bergeron, R.J.; Porter, C.W.

Cancer Research 49(22): 6226-6231


ISSN/ISBN: 0008-5472
PMID: 2804970
Accession: 040625156

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As an antiproliferative strategy, we are using bis(ethyl) derivatives of spermine to suppress polyamine biosynthetic enzyme activity and, thereby, deplete intracellular polyamine pools. Since certain of these analogues have recently been shown to potently increase spermidine/spermine-N1-acetyltransferase activity, we have investigated the relationship of this effect to growth inhibition and polyamine depletion. The cellular effects of N1,N12-bis(ethyl)spermine (BESPM) and two of its homologues, N1,N11-bis(ethyl)norspermine (BENSPM) and N1,N14-bis(ethyl)homospermine (BEHSPM), were compared in L1210 cells following treatments at equimolar concentrations (2 microM) and at concentrations (0.5 microM BEHSPM; 2 microM BESPM, and 20 microM BENSPM) producing comparable intracellular concentrations (2600-3000 pmol/10(6) cells) of the analogues. At 2 microM, BENSPM increased total polyamine N-acetyltransferase activity by 15-fold, BESPM, by 7-fold, and BEHSPM, by only 1.5-fold. These differences were much more exaggerated at comparable intracellular concentrations, where BENSPM increased enzyme activity 31-fold, BESPM, 7-fold, and BEHSPM had no effect. This rank order in effectiveness sharply contrasted effects on cell growth and interference with polyamine biosynthesis, which correlated more with intracellular accumulation of the analogues. At 2 microM, BEHSPM was most effective in suppressing ornithine and S-adenosylmethionine decarboxylases, depleting polyamine pools, and inhibiting cell growth, followed by BESPM and then by BENSPM. Thus, the data indicate that, in L1210 cells, the large increases in spermidine/spermine-N1-acetyltransferase activity produced by the analogues do not appear to contribute significantly to polyamine depletion or to be causally related to inhibition of cell growth. These studies also identify BENSPM as the most potent modulator of spermidine/spermine-N1-acetyltransferase activity thus far studied in cell culture systems. To a large extent, its greater effectiveness over BESPM seems to be attributable to a major increase in prolongation of enzyme half-life (3.9 versus 1.3 h), presumably due to enzyme stabilization caused by differential binding of the analogues at the enzyme active site.

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