Glucocorticoids and polyamine inhibitors synergize to kill human leukemic CEM cells.
Glucocorticoids are well-known apoptotic agents in certain classes of lymphoid cell malignancies. Reduction of intracellular polyamine levels by use of inhibitors that block polyamine synthesis slows or inhibits growth of many cells in vitro. Several such inhibitors have shown efficacy in clinical trials, though the toxicity of some compounds has limited their usefulness. We have tested the effects of combinations of the glucocorticoid dexamethasone (Dex) and two polyamine inhibitors, difluoromethylornithine (DFMO) and methyl glyoxal bis guanylhydrazone (MGBG), on the clonal line of human acute lymphoblastic leukemia cells, CEM-C7-14. Dex alone kills these cells, though only after a delay of at least 24 hours. We also evaluated a partially glucocorticoid-resistant c-Myc-expressing CEM-C7-14 clone. We show that Dex downregulates ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis. Pretreatment with the ODC inhibitor DFMO, followed by addition of Dex, enhances steroid-evoked kill slightly. The combination of pretreatment with sublethal concentrations of both DFMO and the inhibitor of S-adenosylmethionine decarboxylase, MGBG, followed by addition of Dex, results in strong synergistic cell kill. Both the rapidity and extent of cell kill are enhanced compared to the effects of Dex alone. These results suggest that use of such combinations in vivo may result in apoptosis of malignant cells with lower overall toxicity.
Miller
Aaron L
AL
Department of Human Biological Chemistry and Genetics, The University of Texas Medical Branch, Galveston 77550-0645, USA.
Johnson
Betty H
BH
Medh
Rheem D
RD
Townsend
Courtney M
CM
Thompson
E Brad
EB
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division; D003907:Dexamethasone / Q000627:therapeutic use*; D004357:Drug Synergism; D000518:Eflornithine / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D015151:Immunoblotting; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria; D008935:Mitoguazone / Q000627:therapeutic use; D009955:Ornithine Decarboxylase / Q000235:genetics* / Q000378:metabolism*; D065108:Ornithine Decarboxylase Inhibitors; D012313:RNA / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D065108:Ornithine Decarboxylase Inhibitors; D012313:RNA; D003907:Dexamethasone; D009955:Ornithine Decarboxylase; D008935:Mitoguazone; D000518:Eflornithine