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

M. Porosnicu, R. Nimmanapalli, D. Nguyen, E. Worthington, C. Perkins, K. N. Bhalla

Research output: Contribution to journalArticle

84 Scopus citations

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 μM) or As2O3 (0.5 to 2.0 μM) 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-xL, 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.

Original languageEnglish (US)
Pages (from-to)772-778
Number of pages7
JournalLeukemia
Volume15
Issue number5
DOIs
StatePublished - 2001

Keywords

  • AKT
  • ASO
  • Bcl-x
  • Bcr-Abl
  • STI-571

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

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