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Effect of interleukin-1 beta converting enzyme inhibitor on acute
myelogenous leukemia progenitor proliferation
Z Estrov, RA Black, PR Sleath, D Harris, Q Van, R LaPushin, EH Estey and M Talpaz
Department of Bioimmunotherapy, University of Texas M.D. Anderson Cancer
Center, Houston 77030, USA.
Interleukin-1 beta (IL-1 beta) converting enzyme (ICE) is a cysteine
protease that specifically cleaves precursor IL-1 beta to its biologically
active form. Recent studies have also implicated ICE in the induction of
apoptosis in vertebrate cells. Because IL-1 plays a major role in acute
myelogenous leukemia (AML) blast proliferation, we sought to investigate
the effect of ICE inhibition on AML progenitors. To do this, we used
bocaspartyl (benzyl) chloromethylketone (BACMK) an inhibitor designed to
penetrate cells and bind covalently to the active site of ICE. Our
preliminary experiments showed that incubation of activated peripheral
blood cells with 2.5 mumol/L of BAMCK downregulated production of mature
IL-1 beta but had no effect on tumor necrosis factor-alpha. To test the
effects of the inhibitor on AML cells, we first used the OCI/AML3 cell
line. We found that these cells produce IL-1 beta and bind the biotinylated
cytokine and that IL-1 inhibitors, such as IL-1 neutralizing antibodies,
IL-1 receptor antagonist, and soluble IL-1 receptors, specifically inhibit
OCI/AML3 proliferation, indicating that IL-1 beta is an autocrine growth
factor for OCI/AML3 cells. The ICE inhibitor suppressed OCI/AML3 growth in
a dose-dependent manner (at 0.4 to 4 mumol/L) and downregulated mature IL-
1 beta production, as assessed by Western immunoblotting. Similar results
were obtained with marrow aspirates from 16 AML patients. The ICE inhibitor
suppressed proliferation of AML precursors (by up to 78%; mean, 44%) in a
dose-dependent fashion at concentrations ranging from 0.4 to 5 mumol/L but
not proliferation of normal marrow progenitors; the suppressive effect was
reversed by IL-1 beta. Furthermore, incubation of AML cells with 4 mumol/L
BAMCK downregulated the production of mature IL-1 beta, suggesting that the
growth-inhibitory effect is mediated through suppression of the
biologically active cytokine. Our data indicate that inhibition of ICE
suppresses AML blast proliferation and suggest that ICE inhibitors may have
a role in future therapies for AML.
Volume 86,
Issue 12,
pp. 4594-4602,
12/15/1995
Copyright © 1995 by The American Society of Hematology
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