High-dose mitoxantrone induces programmed cell death or apoptosis in human myeloid leukemia cells

Kapil Bhalla, Ana Maria Ibrado, Elena Tourkina, Caroline Tang, Steven Grant, Gloria Bullock, Yue Huang, Vidya Ponnathpur, Mary Ella Mahoney

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

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 μmol/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.

Original languageEnglish (US)
Pages (from-to)3133-3140
Number of pages8
JournalBlood
Volume82
Issue number10
DOIs
StatePublished - 1993

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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