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 kinas e (TK), and K562 tells, with endogenous expression of p210 Bcr-Abl TK, disp lay a high degree of resistance against antileukemic drug-induced apoptosis (G, Fang st al., Blood, 96: 2246-2256. 2000), Present studies demonstrate that treatment with ansamycin antibiotic geldanamycin (GA), or its less tox ic analogue 17-allylamino-17-demethoxygeldanamycin (17-AAG), induces cytoso lic accumulation of cytochrome c and cleavage and activities of caspase-9 a nd c aspase-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-l, 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 apo ptosis of HL-60/Bcr-Abl and K562 cells. These data establish the in vitro a ctivity of CA and 17-AAG against Bcr-Abl-positive leukemic cells and suppor t the in vivo investigation of 17-AAG against Bcr-Abl-positive leukemias.