Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs.
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.
Department of Hematology, Royal Free and University College Medical School, London, United Kingdom.
Dylan T
DT
Jones
Elena
E
Addison
Janet M
JM
North
Mark W
MW
Lowdell
A Victor
AV
Hoffbrand
Atul B
AB
Mehta
Kanagasabai
K
Ganeshaguru
Najeem I
NI
Folarin
R Gitendra
RG
Wickremasinghe
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D018952:Antigens, CD34 / Q000096:biosynthesis; D017209:Apoptosis; D016227:Benzoquinones; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology; D002469:Cell Separation; D002699:Chlorambucil / Q000494:pharmacology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017828:Rifabutin / Q000494:pharmacology / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051746:ZAP-70 Protein-Tyrosine Kinase
D000903:Antibiotics, Antineoplastic; D018952:Antigens, CD34; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D002699:Chlorambucil; D017828:Rifabutin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D014740:Vidarabine; C024352:fludarabine; C001277:geldanamycin