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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. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-05-1603v1 103/5/1855    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Jones, D. T. Articles by Wickremasinghe, R. G. Search for Related Content PubMed PubMed Citation Articles by Jones, D. T. Articles by Wickremasinghe, R. G. Related Collections Hematopoiesis and Stem Cells Immunobiology Neoplasia Apoptosis Signal Transduction Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs Dylan T. Jones, Elena Addison, Janet M. North, Mark W. Lowdell, A. Victor Hoffbrand, Atul B. Mehta, Kanagasabai Ganeshaguru, Najeem I. Folarin, and R. Gitendra Wickremasinghe From the Department of Hematology, Royal Free and University College Medical School, London, United Kingdom. We studied the actions of geldanamycin (GA) and herbimycin A (HMA), inhibitors of the chaperone proteins Hsp90 and GRP94, on B chronic lymphocytic leukemia (CLL) cells in vitro. Both drugs induced apoptosis of the majority of CLL isolates studied. Whereas exposure to 4-hour pulses of 30 to 100 nM GA killed normal B lymphocytes and CLL cells with similar dose responses, T lymphocytes from healthy donors as well as those present in the CLL isolates were relatively resistant. GA, but not HMA, showed a modest cytoprotective effect toward CD34+ hematopoietic 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 of CLL isolates. GA- and HMA-induced apoptosis was preceded by the up-regulation of the stress-responsive chaperones Hsp70 and BiP. Both ansamycins also resulted in down-regulation 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. E. Castro, C. E. Prada, O. Loria, A. Kamal, L. Chen, F. J. Burrows, and T. J. Kipps ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia Blood, October 1, 2005; 106(7): 2506 - 2512. [Abstract] [Full Text] [PDF]

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