Effects of (2R, 5R)-6-heptyne-2,5-diamine, a potent inhibitor of L-ornithine decarboxylase, on rat hepatoma cells cultured in vitro.
DL-alpha-Difluoromethylornithine (F2MeOrn), the most widely-used inhibitor of L-ornithine decarboxylase, has been a useful tool to demonstrate that polyamine biosynthesis is required to maintain maximum rates of cell proliferation. However, in most eukaryotic cell systems, F2MeOrn exerts cytostatic rather than cytotoxic effects. This may be due to the fact that this inhibitor creates only incomplete polyamine deficiency. In particular, F2MeOrn scarcely depletes intracellular spermine levels. We now demonstrate in rat hepatoma tissue culture (HTC) cells that (2R, 5R)-6-heptyne-2,5-diamine, a more potent irreversible inhibitor of L-ornithine decarboxylase than F2MeOrn, decreases the concentrations of all polyamines including spermine. In parallel with the depletion of these amines, there is a progressive decrease in the rate of cell proliferation and in cell viability. Restoration of the intracellular polyamine content, by addition to the medium of polyamines or a high concentration of L-ornithine, the substrate of L-ornithine decarboxylase, further demonstrates that the antiproliferative effects of (2R, 5R)-6-heptyne-2,5-diamine do result from polyamine deficiency. These findings support the concept that polyamines play an essential function in the cell division processes and emphasize the vital function of spermine in mammalian cells.
D012437:Adenosylmethionine Decarboxylase / Q000378:metabolism; D000480:Alkynes; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003959:Diamines / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology*; D065108:Ornithine Decarboxylase Inhibitors; D011700:Putrescine / Q000378:metabolism; D051381:Rats; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism
D000480:Alkynes; D003959:Diamines; D065108:Ornithine Decarboxylase Inhibitors; D013096:Spermine; C039613:6-heptyne-2,5-diamine; D012437:Adenosylmethionine Decarboxylase; D013095:Spermidine; D011700:Putrescine