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Sensitivity and Resistance to Therapy

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

Leukemia volume 15, pages 772–778 (2001)Cite this article

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.

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Authors and Affiliations

  1. Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL, USA

    M Porosnicu, D Nguyen, E Worthington & C Perkins

  2. Interdisciplinary Oncology Program, Moffitt Cancer Center, University of South Florida, Tampa, FL, USA

    R Nimmanapalli & KN Bhalla

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Porosnicu, M., Nimmanapalli, R., Nguyen, D. et al. Co-treatment with As2O3 enhances selective cytotoxic effects of STI-571 against Bcr-Abl-positive acute leukemia cells. Leukemia 15, 772–778 (2001). https://doi.org/10.1038/sj.leu.2402104

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