Glucocorticoids and polyamine inhibitors synergize to kill human leukemic CEM cells

Neoplasia : an International Journal for Oncology Research
Aaron L MillerE Brad Thompson

Abstract

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 ...Continue Reading

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Citations

Sep 24, 2004·International Journal of Cancer. Journal International Du Cancer·Eun-Joo NohBon-Hong Min
Oct 6, 2005·Journal of Cellular and Molecular Medicine·Nikolaus Seiler, Francis Raul
May 8, 2003·The Journal of Immunology : Official Journal of the American Association of Immunologists·Heui-Young RyuDavid H Sherr
Aug 29, 2003·The Journal of Steroid Biochemistry and Molecular Biology·M Scott WebbE Brad Thompson

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