Co-treatment with As2O3 enhances selective cytotoxic effects of STI-571 against Brc-Abl-positive acute leukemia cells

Leukemia. 2001 May;15(5):772-8. doi: 10.1038/sj.leu.2402104.

Abstract

By inhibiting the tyrosine kinase (TK) activity of Bcr-Abl, STI-571 induces differentiation and apoptosis of HL-60/Bcr-Abl (with ectopic expression of p185 Bcr-Abl) and K562 (containing endogenous expression of p210 Bcr-Abl) but not of the control HL-60 cells. Treatment with arsenic trioxide (As2O3) lowers Bcr-Abl protein levels and induces apoptosis of the Bcr-Abl-positive leukemic blasts (Blood 2000; 95: 1014). Here, we demonstrate that compared to treatment with STI-571 (0.25 to 1.0 microM) or As2O3 (0.5 to 2.0 microM) alone, combined treatment with As2O3 and STI-571 induced significantly more apoptosis of HL-60/Bcr-Abl and K562 but not HL-60/neo cells (P < 0.05). Combined treatment with As2O3 and STI-571 also resulted in greater reductions in the levels of Bcl-x(L), XIAP and Akt, and inhibition of Akt kinase activity. Co-treatment with As2O3 inhibited STI-571-induced hemoglobin, which was associated with the cleavage and downregulation of GATA-1 transcription factor involved in erythroid differentiation. These data demonstrate that a treatment strategy which combines an agent that lowers Bcr-Abl levels, eg As2O3, with an agent that inhibits Bcr-Abl TK activity, eg STI-571, can potently induce apoptosis and differentiation of Bcr-Abl-positive human leukemic cells.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects
  • Arsenic Trioxide
  • Arsenicals / administration & dosage*
  • Benzamides
  • Drug Synergism
  • Fusion Proteins, bcr-abl / analysis*
  • Hemoglobins / analysis
  • Humans
  • Imatinib Mesylate
  • Leukemia / drug therapy*
  • Leukemia / pathology
  • Macrophage-1 Antigen / analysis
  • Oxides / administration & dosage*
  • Piperazines / administration & dosage*
  • Protein-Serine-Threonine Kinases*
  • Proteins / analysis
  • Proto-Oncogene Proteins / analysis
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / analysis
  • Pyrimidines / administration & dosage*
  • Tumor Cells, Cultured
  • X-Linked Inhibitor of Apoptosis Protein
  • bcl-X Protein

Substances

  • Arsenicals
  • BCL2L1 protein, human
  • Benzamides
  • Hemoglobins
  • Macrophage-1 Antigen
  • Oxides
  • Piperazines
  • Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrimidines
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • bcl-X Protein
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Arsenic Trioxide