Correlation between the inhibition of cell growth by accumulated polyamines and the decrease of magnesium and ATP.
The mechanism of the antiproliferation effect of spermidine and spermine was studied using a cell culture system of mouse FM3A cells. The addition of either 10 mM spermidine or 2 mM spermine to the growth medium containing 0.9 mM Mg2+ greatly inhibited cell growth (more than 90%). A decrease in the Mg2+ concentration to 50 microM in the growth medium, but without the polyamine addition, did not influence cell growth. However, the concentrations of spermidine and spermine necessary for the inhibition of cell growth when cells were cultured in the presence of 50 microM Mg2+ were much smaller (2 mM spermidine and 0.15 mM spermine). Nevertheless, the amount of polyamines accumulating in cells which could cause the inhibition of cell growth was almost the same, regardless of the large difference in the added polyamine concentrations. At the early stage of polyamine accumulation, the inhibition of cell growth correlated with the decrease of Mg2+ content, but not with a decrease of the ATP content. The decrease in Mg2+ content correlated well with the inhibition of macromolecular synthesis, especially protein synthesis. Thus, the inhibition of cell growth at the early stage of polyamine accumulation was thought to be due to the inactivation of ribosomes through the replacement of Mg2+ on magnesium-binding sites by polyamines. The decrease in Mg2+ content was mainly caused by the inhibition of Mg2+ transport by polyamines. At the later stage of polyamine accumulation, a decrease in ATP content was also observed. This was followed by swelling of the mitochondria, which may be a symptom of the subsequent cell death.
He
Y
Y
Faculty of Pharamaceutical Sciences, Chiba University, Japan.
Kashiwagi
K
K
Fukuchi
J
J
Terao
K
K
Shirahata
A
A
Igarashi
K
K
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D007700:Kinetics; D008274:Magnesium / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008854:Microscopy, Electron; D011073:Polyamines / Q000378:metabolism / Q000494:pharmacology*; D013095:Spermidine / Q000494:pharmacology; D013096:Spermine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D011073:Polyamines; D013096:Spermine; D000255:Adenosine Triphosphate; D008274:Magnesium; D013095:Spermidine