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Acute Leukemias

Targeting Hsp90 by 17-AAG in leukemia cells: mechanisms for synergistic and antagonistic drug combinations with arsenic trioxide and Ara-C

Leukemia volume 20, pages 610–619 (2006)Cite this article

Abstract

17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a new anticancer agent currently in clinical trials. The ability of 17-AAG to abrogate the function of heat-shock protein Hsp90 and modulate cellular sensitivity to anticancer agents has prompted recent research to use this compound in drug combination therapy. Here we report that 17-AAG has striking opposite effects on the activity of arsenic trioxide (ATO) and ara-C. Combination of 17-AAG with ATO exhibited a synergistic effect in leukemia cells, whereas coincubation of 17-AAG and ara-C showed antagonistic activity. Mechanistic studies revealed that ATO exerted cytotoxic action by reactive oxygen species generation, and activated Akt survival pathway. 17-AAG abrogated Akt activation and enhanced the activity of ATO. In contrast, treatment of leukemia cells with 17-AAG caused a G1 arrest, a decrease in DNA synthesis and reduced ara-C incorporation into DNA, leading to antagonism. The ability of 17-AAG to enhance the antileukemia activity of ATO was further demonstrated in primary leukemia cells isolated from patients with acute myeloid leukemia and chronic lymphocytic leukemia, including cells from refractory patients. Our data suggest that combination of 17-AAG and ATO may be an effective therapeutic regimen. Caution should be exercised in using 17-AAG together with ara-C, as their combination effects are schedule dependent.

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Acknowledgements

This work was supported in part by Grants CA85563, CA109041, CA100428, CA100632 and CA16672 from the National Cancer Institute, the National Institutes of Health. JSC is a recipient of fellowships from the American Legion Auxiliary and the Sowell-Huggins Families.

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Authors and Affiliations

  1. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    H Pelicano, J S Carew & P Huang

  2. Department of Blood and Marrow Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    T J McQueen & M Andreeff

  3. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    W Plunkett

  4. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M J Keating

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  1. H Pelicano
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Correspondence to P Huang.

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Pelicano, H., Carew, J., McQueen, T. et al. Targeting Hsp90 by 17-AAG in leukemia cells: mechanisms for synergistic and antagonistic drug combinations with arsenic trioxide and Ara-C. Leukemia 20, 610–619 (2006). https://doi.org/10.1038/sj.leu.2404140

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