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

Leukemia. 2001 Oct;15(10):1537-43. doi: 10.1038/sj.leu.2402257.


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.

Publication types

  • Comparative Study

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Benzoquinones
  • Doxorubicin / pharmacology
  • Drug Interactions
  • Drug Resistance
  • Fusion Proteins, bcr-abl / biosynthesis
  • Fusion Proteins, bcr-abl / drug effects*
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Humans
  • Lactams, Macrocyclic
  • Leukemia / metabolism
  • Leukemia / pathology*
  • Paclitaxel / pharmacology
  • Quinones / pharmacology*
  • Transfection
  • Tumor Cells, Cultured / drug effects


  • Antineoplastic Agents
  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Quinones
  • Doxorubicin
  • Fusion Proteins, bcr-abl
  • Paclitaxel
  • geldanamycin