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

M. V. Blagosklonny, T. Fojo, K. N. Bhalla, J. S. Kim, J. B. Trepel, W. D. Figg, Y. Rivera, L. M. Neckers

Research output: Contribution to journalArticle

124 Scopus citations

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 nΜ 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.

Original languageEnglish (US)
Pages (from-to)1537-1543
Number of pages7
JournalLeukemia
Volume15
Issue number10
DOIs
StatePublished - 2001

Keywords

  • Bcr-Abl
  • Chemotherapy
  • Cytoprotection
  • Gendanamycin
  • HSP90
  • Oncogenes

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

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