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

The Bcr-Abl fusion protein drives leukemogenesis and can render leukemia ce lls resistant to conventional chemotherapy. Geldanamycin (GA), a drug which destabilizes Hsp90-associated proteins, depletes cells of Bcr-Abl, an Hsp9 0 client, but not of Abl. Both HL60 cells transfected with Bcr-Abl and natu rally Ph-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 fragmentati on, 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, S TI 571 did not antagonize the cytotoxic effects of DOX in parental HL60 cel ls. These results indicate that sensitization of Bcr-Abl-expressing cells, but not desensitization of HL60 cells, depends on inhibition of Bcr-Abl. Th us, GA differentially affects leukemia cells depending on their Bcr-Abl exp ression and selectively increases apoptosis in Bcr-Abl-expressing cells.