Effect of combined treatment with interleukin-3 and interleukin-6 on 4-hydroperoxycyclophosphamide-induced programmed cell death or apoptosis in human myeloid leukemia cells

G. Bullock, C. Tang, E. Tourkina, A. M. Ibrado, J. Lutzky, Y. Huang, M. E. Mahoney, Kapil Bhalla

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

In autologous bone marrow transplantation in patients with acute myeloid leukemia (AML), 4-hydroperoxycyclophosphamide (4-HC) is a commonly used ex vivo purging agent for leukemic blasts. In the present report, we demonstrate that exposure to high concentrations of 4-HC for 1 hour, as used in ex vivo bone marrow purging, produces internucleosomal DNA fragmentation characteristic of apoptosis, or programmed cell death (PCD), in human myeloid leukemia HL60 cells. Lower concentrations of 4-HC (10, 20, or 50 μM/L) failed to cause this effect, while higher concentrations (≥2200 μM/L) produced random DNA fragmentation. 4-HC-mediated internucleosomal DNA fragmentation was associated with a marked induction in c-jun and significant reductions in bcl-2 and c-myc oncogene expressions. A combined treatment with interleukin-3 (IL-3) plus IL-6 for 18 hours before an additional, 1-hour concurrent treatment with 4-HC (100 μM/L) significantly increased 4-HC-induced DNA fragmentation as well as colony growth inhibition of HL60 cells. The effects of cotreatment with IL-3 plus IL-6 were also associated with a further, modest decrease in bcl-2 and c-myc and augmentation of c-jun expression. These findings highlight an alternative mechanism of 4-HC-induced leukemic cell death that can be potentially enhanced by cotreatment with IL-3 plus IL-6.

Original languageEnglish (US)
Pages (from-to)1640-1647
Number of pages8
JournalExperimental Hematology
Volume21
Issue number13
StatePublished - Dec 1 1993

Keywords

  • 4-HC
  • Apoptosis
  • bcl-2
  • Interleukin-3
  • Interleukin-6

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

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