Effect of S'-Adenosyl-1,12-diamino-3-thio-9-azadodecane, a Multisubstrate Adduct Inhibitor of Spermine Synthase, on Polyamine Metabolism in Mammalian Cells

Anthony E. Pegg, Rita Wechter, Richard Poulin, Patrick M. Woster, James K. Coward

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

The effects of the potent spermine synthase inhibitor S-adenosyl-1,12-diamino-3-thio-9-aza-dodecane (AdoDatad) on polyamine biosynthesis have been studied in transformed mouse fibroblasts (SV 3T3 cells) and in mouse leukemia cells (L1210). A dose-dependent decrease in intracellular spermine concentration was observed in both cell lines when grown in the presence of the inhibitor. A major difference in the effects seen in these two cell lines was the cytotoxicity observed in L1210 cells exposed to the inhibitor, which contrasted with little or no effects on growth of SV 3T3 cells treated similarly. Oxidative metabolism of the drug in L1210 cells was suggested by the fact that addition of aminoguanidine, an amine oxidase inhibitor, to the cell cultures ablated the cytotoxic effects of the inhibitor. Complete analysis of intracellular polyamines was carried out, together with analysis of S-adenosylmethionine, decarboxylated S-adenosyl-methionine, and the inhibitor. These analyses revealed that, although the inhibitor had a dramatic effect on spermine biosynthesis in the cells studied, a compensatory increase in spermidine biosynthesis was observed. This resulted in no change in total polyamine concentrations in cells treated with inhibitors of either spermine synthase or spermidine synthase (Pegg et al., 1982) alone or in combination. In all cases, the concentration of the aminopropyl donor decarboxylated S-adenosylmethionine increased dramatically, thus allowing for the observed maintenance of total polyamine levels even in the presence of either one or both potent inhibitors of the aminopropyltransferases. Oxidative metabolism of the inhibitor complicates the interpretation of experiments carried out in the absence of amine oxidase inhibitors such as aminoguanidine. In addition, the results suggest that the extent of polyamine depletion achieved with AdoDatad and other amino-propyltransferase inhibitors could be significantly improved by combination with specific inhibitors of S-adenosylmethionine decarboxylase, which would prevent the compensatory increase in the decarboxylated S-adenosylmethionine pool size.

Original languageEnglish (US)
Pages (from-to)8446-8453
Number of pages8
JournalBiochemistry
Volume28
Issue number21
DOIs
StatePublished - Jan 1 1989

All Science Journal Classification (ASJC) codes

  • Biochemistry

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