Synergistic inhibition of the glucocorticoid receptor by radicicol and benzoquinone ansamycins.
Radicicol (RAD) and the benzoquinone ansamycin geldanamycin (GA) are potential anticancer drugs known to inhibit heat shock protein 90 (hsp90) and, therefore, 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 benzoquinone ansamycins. All compounds efficiently abolished GR-dependent transactivation. Surprisingly, whenever one of the ansamycins was applied in combination with RAD, synergistic inhibition of GR-dependent transcription and of hormone binding of GR was observed. In contrast, combination of two ansamycins showed no synergy. These findings suggest synergism within the hsp90 dimer and may open new ways to explore hsp90 as therapeutic target.
Rosenhagen
M C
MC
Max Planck Institute of Psychiatry, Munich, Germany.
Young
J C
JC
Wochnik
G M
GM
Herr
A S
AS
Schmidt
U
U
Hartl
F U
FU
Holsboer
F
F
Rein
T
T
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016227:Benzoquinones; D004357:Drug Synergism; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D047029:Lactams, Macrocyclic; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D011809:Quinones / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000235:genetics; D017828:Rifabutin / Q000031:analogs & derivatives; D029701:Saccharomyces cerevisiae Proteins; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D016227:Benzoquinones; C074510:HSP82 protein, S cerevisiae; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D007783:Lactones; D018942:Macrolides; D011809:Quinones; D011965:Receptors, Glucocorticoid; D029701:Saccharomyces cerevisiae Proteins; D017828:Rifabutin; C020754:herbimycin; C035359:monorden; C001277:geldanamycin