Modulation of Hsp90 function by ansamycins sensitizes breast cancer cells to chemotherapy-induced apoptosis in an RB- and schedule-dependent manner -See The Biology Behind: E. A. Sausville, combining cytotoxics and 17-allylamino, 17-demethoxygeldanamycin: Sequence and tumor biology matters. Clin. Cancer Res., 7: 2155-2158, 2001.

17-allyl-aminogeldanamycin (17-AAG) is an ansamycin antibiotic that binds t o a highly conserved pocket in the Hsp90 chaperone protein and inhibits its function. Hsp90 is required for the refolding of proteins during cellular stress and the conformational maturation of certain signaling proteins. 17- AAG has antitumor activity in cell culture and animal xenograft models and is currently in clinical trial. It causes an RB-dependent G(1) arrest, diff erentiation, and apoptosis. RB-negative cells arrest in mitosis and undergo apoptosis. Hsp90 plays an important role in the cellular response to envir onmental stress. Therefore, we tested whether the regulation of Hsp90 funct ion by 17-AAG could sensitize cells to cytotoxic agents. 17-AAG sensitized tumor cells to Taxol and doxorubicin. Taxanes cause growth arrest in mitosi s and apoptosis. The addition of 17-AAG to cells after exposure to Taxol si gnificantly increased both the activation of caspases 9 and 3 and apoptosis . In cells with intact RB, exposure to 17-AAG before Taxol resulted in G(1) arrest and abrogated apoptosis. Schedule dependence was not seen in cells with mutated RB, because both agents blocked cells in mitosis. Schedule- or RB-dependence was also not observed when cells were treated with 17-AAG an d doxorubicin, a DNA-intercalating agent that acts on different phases of t he cell cycle. These findings suggest that inhibition of Hsp90 function by 17-AAG enhances the administration and the RB status significantly influenc e efficacy.