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The Hsp90 inhibitor geldanamycin selectively sensitizes Bcr-Abl-expressing leukemia cells to cytotoxic chemotherapy

Leukemia volume 15, pages 1537–1543 (2001)Cite this article

Abstract

The Bcr-Abl fusion protein drives leukemogenesis and can render leukemia cells resistant to conventional chemotherapy. Geldanamycin (GA), a drug which destabilizes Hsp90-associated proteins, depletes cells of Bcr-Abl, an Hsp90 client, but not of Abl. Both HL60 cells transfected with Bcr-Abl and naturally Ph1-positive K562 leukemia cells are resistant to most cytotoxic drugs, but were found to be sensitive to GA. Furthermore, GA sensitized Bcr-Abl-expressing cells to doxorubicin (DOX) and paclitaxel (PTX). In contrast, in parental HL60 cells, 90 nM GA inhibited PARP cleavage, nuclear fragmentation, and cell death caused by 500 ng/ml DOX. Like GA, STI 571 (an inhibitor of the Abl kinase) sensitized Bcr-Abl-expressing cells to DOX. Unlike GA, STI 571 did not antagonize the cytotoxic effects of DOX in parental HL60 cells. These results indicate that sensitization of Bcr-Abl-expressing cells, but not desensitization of HL60 cells, depends on inhibition of Bcr-Abl. Thus, GA differentially affects leukemia cells depending on their Bcr-Abl expression and selectively increases apoptosis in Bcr-Abl-expressing cells.

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Authors and Affiliations

  1. Department of Developmental Therapeutics, Medicine Branch, National Cancer Institute, NIH, Bethesda and Rockville, MD, USA

    MV Blagosklonny, T Fojo, J-S Kim, JB Trepel & WD Figg

  2. Department of Cell and Cancer Biology, Medicine Branch, National Cancer Institute, NIH, Bethesda and Rockville, MD, USA

    Y Rivera & LM Neckers

  3. Moffitt Cancer Center, Tampa, FL, USA

    KN Bhalla

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  1. MV Blagosklonny
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Blagosklonny, M., Fojo, T., Bhalla, K. et al. The Hsp90 inhibitor geldanamycin selectively sensitizes Bcr-Abl-expressing leukemia cells to cytotoxic chemotherapy. Leukemia 15, 1537–1543 (2001). https://doi.org/10.1038/sj.leu.2402257

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