Ability of bisbenzylputrescine and propanediamine analogs to modulate the intracellular polyamine pool of P388D1 cells.
The effects of a series of bisbenzyldiamine analogs have been tested on P388D1 cell line in vitro. Their effects on cell growth, polyamine oxidase (PAO) activity and intracellular polyamine content were determined. The cytotoxicity tests were performed in culture medium supplemented with 100 micromol/L aminoguanidine (I), 100 micromol/L aminoguanidine and 100 micromol/L N,N'-bis(2,3-butadienyl)-1,4-butanediamine (MDL 72,527) (II), and finally 100 micromol/L aminoguanidine and 200 micromol/L D,L-difluoromethylornithine (DFMO) (III). The IC50 values under conditions I and III were similar, suggesting that inhibition of ornithine decarboxylase by DFMO did not affect the biological effect of our derivatives. Spermine and spermidine remained nontoxic in conditions I and III. However in the condition II, the toxicity of all tested compounds (excepted spermidine) was increased, suggesting that the inhibition of cellular PAO increased their toxicity. The enzymatic test of PAO showed that at high doses inhibition of this enzyme by putrescine analogs occurred, while the N-methylated propanediamine derivative increased the enzyme activity; however, these results do not correlate with cytotoxicity tests. When these derivatives were incubated for 48 h with the cells, all of them increased the cell content in putrescine (approximately 160%) and spermine (approximately 145%) and decreased the spermidine content (approximately 75%) without any modification of the total amount of polyamine. The correlation between the cytotoxic results and the intracellular polyamine determination shows that the increase in spermine content along with the inhibition of retroconverting PAO enzyme increases the toxic effect of tested compounds (including spermine), suggesting that spermine toxicity is more important in the absence of intracellular oxidation processes.
Badolo
L
L
Laboratoire de Chimie Bioanalytique, de Toxicologie et de Chimie Physique Appliquée, Institut de Pharmacie, Université Libre de Bruxelles, Belgium.
Hanocq
M
M
Dubois
J
J
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007941:Leukemia P388 / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism*; D011437:Propylamines / Q000737:chemistry / Q000494:pharmacology*; D011700:Putrescine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000097667:Polyamine Oxidase
D004791:Enzyme Inhibitors; D009955:Ornithine Decarboxylase; D065108:Ornithine Decarboxylase Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D011437:Propylamines; D011700:Putrescine; D000097667:Polyamine Oxidase