Blood. 2003 Oct 23 [Epub ahead of print].
Geldanamycin and Herbimycin A induce apoptotic killing of B-chronic lymphocytic leukemia cells and augment their sensitivity to cytotoxic drugs.
Jones DT, Addison E, North JM, Lowdell MW, Hoffbrand AV, Mehta AB, Ganeshaguru K, Folarin NI, Wickremasinghe RG.
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 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.
J Nat Prod. 2003 Oct;66(10):1313-7.
Isolation and Characterization of New Epothilone Analogues from Recombinant Myxococcus xanthus Fermentations.
Starks CM, Zhou Y, Liu F, Licari PJ.
Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, California 94545.
Nine new epothilone analogues (6-8, 10, 11a, 11b, 12, 13, and 15) were isolated from fermentations of Myxococcus xanthus strains engineered with modified polyketide synthase genes. The epothilone structures were elucidated primarily through interpretation of 1D and 2D NMR data. 4-Desmethyl-10,11-didehydroepothilone D (6) displayed activity against several tumor cell lines, including a multi-drug-resistant cell line. |
