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High-dose mitoxantrone induces programmed cell death or apoptosis in human
myeloid leukemia cells
K Bhalla, AM Ibrado, E Tourkina, C Tang, S Grant, G Bullock, Y Huang, V Ponnathpur and ME Mahoney
Division of Hematology/Oncology, Medical University of South Carolina,
Charleston 29425.
Mitoxantrone has been shown in vitro to exhibit a steep dose-response
relationship with respect to the clonogenic survival of acute myeloid
leukemia cells. In this report, we show that 1-hour exposure of human
myeloid leukemia HL-60 and KG-1 cells to mitoxantrone concentrations
ranging between 0.1 and 10.0 mumol/L induced internucleosomal DNA
fragmentation of approximately 200-bp integer multiples, characteristic of
cells undergoing programmed cell death (PCD) or apoptosis.
Mitoxantrone-mediated PCD was associated with a steep inhibition of the
clonogenic survival of the leukemic cells. In addition, intracellularly,
mitoxantrone-induced PCD was associated with a marked induction of c-jun
and significant repression of c-myc and BCL-2 oncogenes. Pretreatment with
the protein kinase C stimulator phorbol myristate acetate enhanced
mitoxantrone-induced internucleosomal DNA fragmentation, whereas protein
kinase C inhibitors staurosporine and H7 had no effect. These findings
suggest that PCD is a potential mechanism underlying the steep
dose-response relationship of mitoxantrone to the inhibition of clonogenic
survival of acute myeloid leukemia cells.
Volume 82,
Issue 10,
pp. 3133-3140,
11/15/1993
Copyright © 1993 by The American Society of Hematology
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