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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1855-1861.
Prepublished online as a Blood First Edition Paper on October 23, 2003; DOI 10.1182/blood-2003-05-1603.
Submitted May 19, 2003
Accepted October 17, 2003
Geldanamycin and Herbimycin A induce apoptotic killing of B-chronic lymphocytic leukemia cells and augment their sensitivity to cytotoxic drugs
Dylan T Jones, Elena Addison, Janet M North, Mark W Lowdell, A V Hoffbrand, Atul B Mehta, Kanagasabai Ganeshaguru, Najeem I Folarin, and R G Wickremasinghe*
Hematology, Royal Free and University College Medical School, London, United Kingdom
* Corresponding author; email: r.wickremasinghe{at}rfc.ucl.ac.uk.
We studied the actions of geldanamycin (GA) and herbimycin A (HMA), inhibitors of the chaperone proteins Hsp90 and GRP94, on B-chronic lymphocytic leukaemia (CLL) cells in vitro. Both drugs induced apoptosis of the majority of CLL isolates studied. Whereas exposure to 4h pulses of 30 to 100 nM GA killed normal B lymphocytes and CLL cells with similar dose responses, T lymphocytes from normal donors as well as those present in the CLL isolates were relatively resistant. GA, but not HMA, showed a modest cytoprotective effect towards CD34+ hemopoietic progenitors from normal bone marrow. The ability of bone marrow progenitors to form hematopoietic colonies was unaffected by pulse exposures to GA. Both GA and HMA synergized with chlorambucil and fludarabine in killing a subset o f CLL isolates. GA- and HMA-induced apoptosis was preceded by the upregulation of the stress-responsive chaperones Hsp70 and BiP. Both ansamycins also resulted in downregulation of Akt protein kinase, a modulator of cell survival. The relative resistance of T lymphocytes and of CD34+ bone marrow progenitors to GA coupled with its ability to induce apoptosis following brief exposures and to synergize with cytotoxic drugs warrant further investigation of ansamycins as potential therapeutic agents in CLL.
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