Diphtheria toxin fused to granulocyte-macrophage colony-stimulating factor and Ara-C exert synergistic toxicity against human AML HL-60 cells

Caryn N. Kim, Kapil Bhalla, Robert J. Kreitman, Mark C. Willingham, Philip Hall, Edward P. Tagge, Tao Jia, Authur E. Frankel

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Human granulocyte-macrophage colony-stimulating factor fused to truncated diphtheria toxin (DT388-GM-CSF) sensitized wild-type and Bcl2- overexpressing HL60 human leukemia cells to intoxication by Ara-C based on proliferation and clonogenic assays. The toxin/drug combination showed dramatic synergistic toxicity with combination indices of < 0.1. Synergy was not seen with two other protein synthesis inhibiting drugs - ricin and cycloheximide nor with GMCSF alone: No changes in Ara-C incorporation into cellular DNA or cell cycle occupancy were seen. As compared to exposure to DT388-GM-CSF or Ara-C alone, co-treatment produced significant increases in cytosolic accumulation of cytochrome c, a higher percentage of cells with loss of mitochondrial membrane potential and an increase in reactive oxygen species and morphologic changes of apoptosis, and a greater induction of poly(ADP-ribose) polymerase (PARP) and DNA fragmentation factor 45 (DFF45) cleavage activities of caspase 3. Co-treatment did not significantly alter Bc12, Bcl-X(L), Bax or Fas receptor (FasR), but modestly increased Fas ligand (FasL) protein. These finding suggest that co-treatment with DT388-GM-CSF may lead to a lowered apoptotic threshold and clonogenic survival of human AML blasts due to Ara-C. These observations also suggest that clinical trials of combination therapy may be warranted in patients with AML.

Original languageEnglish (US)
Pages (from-to)527-538
Number of pages12
JournalLeukemia Research
Volume23
Issue number6
DOIs
StatePublished - Jun 1 1999

Keywords

  • Ara-C
  • Diphtheria toxin
  • GMCSF receptor
  • Myeloid leukemia cells

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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