Targeting Hsp90 by 17-AAG in leukemia cells: Mechanisms for synergistic and antagonistic drug combinations with arsenic trioxide and Ara-C

摘要: 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a new anticancer agent currently in clinical trials. The ability of 17-AAG to abrogate the function heat-shock protein Hsp90 and modulate cellular sensitivity agents has prompted recent research use this compound drug combination therapy. Here we report that striking opposite effects on activity arsenic trioxide (ATO) ara-C. Combination with ATO exhibited synergistic effect leukemia cells, whereas coincubation ara-C showed antagonistic activity. Mechanistic studies revealed exerted cytotoxic action by reactive oxygen species generation, activated Akt survival pathway. abrogated activation enhanced ATO. In contrast, treatment cells caused G1 arrest, decrease DNA synthesis reduced incorporation into DNA, leading antagonism. enhance antileukemia was further demonstrated primary isolated from patients acute myeloid chronic lymphocytic leukemia, including refractory patients. Our data suggest may be an effective therapeutic regimen. Caution should exercised using together ara-C, as their are schedule dependent.