Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts.
HL-60/Bcr-Abl cells, with ectopic expression of p185 Bcr-Abl tyrosine kinase (TK), and K562 cells, with endogenous expression of p210 Bcr-Abl TK, display a high degree of resistance against antileukemic drug-induced apoptosis (G. Fang et al., Blood, 96: 2246-2256, 2000). Present studies demonstrate that treatment with ansamycin antibiotic geldanamycin (GA), or its less toxic analogue 17-allylamino-17-demethoxygeldanamycin (17-AAG), induces cytosolic accumulation of cytochrome c and cleavage and activities of caspase-9 and caspase-3, triggering apoptosis of HL-60/Bcr-Abl and K562 cells. GA or 17-AAG down-regulated intracellular Bcr-Abl and c-Raf protein levels, as well as reduced Akt kinase activity. Similar to Raf-1, v-Src, and Her-2-neu, Bcr-Abl TK has chaperone association with heat shock protein 90 (Hsp90). By binding and inhibiting Hsp90, GA or 17-AAG treatment shifted the binding of Bcr-Abl from Hsp90 to Hsp70 and induced the proteasomal degradation of Bcr-Abl, because cotreatment with proteasome inhibitor PSC341 reduced both GA (or 17-AAG)-mediated down-regulation of Bcr-Abl levels and inhibited apoptosis of HL-60/Bcr-Abl and K562 cells. These data establish the in vitro activity of GA and 17-AAG against Bcr-Abl-positive leukemic cells and support the in vivo investigation of 17-AAG against Bcr-Abl-positive leukemias.
Interdisciplinary Oncology Program, Moffitt Cancer Center, University of South Florida, Tampa 33612, USA.
R
R
Nimmanapalli
E
E
O'Bryan
K
K
Bhalla
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones; D002454:Cell Differentiation / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D018922:HL-60 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006454:Hemoglobins / Q000096:biosynthesis; D006801:Humans; D020014:K562 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D047029:Lactams, Macrocyclic; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding / Q000187:drug effects; D011809:Quinones / Q000494:pharmacology*; D017828:Rifabutin / Q000031:analogs & derivatives / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D006454:Hemoglobins; D047029:Lactams, Macrocyclic; D009097:Multienzyme Complexes; D011809:Quinones; D017828:Rifabutin; C112765:tanespimycin; D016044:Fusion Proteins, bcr-abl; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C001277:geldanamycin