Diethylglyoxal bis(guanylhydrazone), a potent inhibitor of mammalian S-adenosylmethionine decarboxylase. Effects on cell proliferation and polyamine metabolism in L1210 leukemia cells.
The polyamines are cell constituents essential for growth and differentiation. S-Adenosylmethionine decarboxylase (AdoMetDC) catalyzes a key step in the polyamine biosynthetic pathway. Methylglyoxal bis(guanylhydrazone) (MGBG) is an anti-leukemic agent with a strong inhibitory effect against AdoMetDC. However, the lack of specificity limits the usefulness of MGBG. In the present report we have used an analog of MGBG, diethylglyoxal bis(guanylhydrazone) (DEGBG), with a much greater specificity and potency against AdoMetDC, to investigate the effects of AdoMetDC inhibition on cell proliferation and polyamine metabolism in mouse L1210 leukemia cells. DEGBG was shown to effectively inhibit AdoMetDC activity in exponentially growing L1210 cells. The inhibition of AdoMetDC was reflected in a marked decrease in the cellular concentrations of spermidine and spermine. The concentration of putrescine, on the other hand, was greatly increased. Treatment with DEGBG resulted in a compensatory increase in the synthesis of AdoMetDC demonstrating an efficient feedback control. Cells seeded in the presence of DEGBG ceased to grow after a lag period of 1-2 days, indicating that the cells contained an excess of polyamines which were sufficient for one or two cell cycles in the absence of polyamine synthesis. The present results indicate that analogs of MGBG, having a greater specificity against AdoMetDC, might be valuable for studies concerning polyamines and cell proliferation.
Svensson
F
F
Department of Physiology and Biophysics, University of Lund, Sweden.
Kockum
I
I
Persson
L
L
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005246:Feedback; D007939:Leukemia L1210 / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008935:Mitoguazone / Q000031:analogs & derivatives* / Q000494:pharmacology; D011073:Polyamines / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D011073:Polyamines; C056522:diethylglyoxal bis(guanylhydrazone); D012437:Adenosylmethionine Decarboxylase; D008935:Mitoguazone