Difluoromethylornithine enhances the uptake of methylglyoxal-bis(guanylhydrazone) prior to inhibiting leukemic cell proliferation.
Difluoromethylornithine (DFMO) is a nonreversible inhibitor of ornithine decarboxylase (ODC), the initial rate-limiting enzyme in the polyamine biosynthetic pathway. When HL60 leukemic cells were incubated in the presence of concentrations of DFMO from 0.05 mM to 5 mM, there was a concentration-dependent inhibition of ODC activity apparent within 24 h. Likewise, cellular polyamine levels were reduced by the presence of DFMO in a concentration-dependent manner after 4 days. The growth of cells incubated with 0.5 mM or greater was inhibited after 3-4 cell doublings. When the concentration of DFMO was less than 0.5 mM, growth was not inhibited. Methylglyoxal-bis(guanylhydrazone) (MGBG) uptake was enhanced in cells treated with concentrations of 0.05-0.5 mM DFMO, but not enhanced in cells treated with DFMO concentrations of 1 mM or greater. DFMO-induced cellular polyamine depletion does enhance MGBG uptake into HL60 cells, but treatment with high concentrations of DFMO, which deplete polyamines to the extent that growth is inhibited, negate this effect.
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D000518:Eflornithine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology; D008935:Mitoguazone / Q000378:metabolism*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism; D011700:Putrescine / Q000378:metabolism
D011073:Polyamines; D009955:Ornithine Decarboxylase; D008935:Mitoguazone; D011700:Putrescine; D000518:Eflornithine