Synergistic inhibition of the glucocorticoid receptor by radicicol and benzoquinone ansamycins

Radicicol (RAD) and the benzoquinone ansamycin geldanamycin (GA) are potent ial anticancer drugs known to inhibit heat shock protein 90 (hsp90) and, th erefore, the activation of proteins dependent on its function such as proto -oncogenic kinases and nuclear receptors. Using the glucocorticoid receptor (GR) as a model system we analysed the effects of RAD and various benzoqui none ansamycins. Ali compounds efficiently abolished GR-dependent transacti vation. Surprisingly, whenever one of the ansamycins was applied in combina tion with RAD, synergistic inhibition of GR-dependent transcription and of hormone binding of GR was observed. in contrast, combination of two ansamyc ins showed no synergy. These findings suggest synergism within the hsp90 di mer and may open new ways to explore hsp90 as therapeutic target.