BACKGROUND: We determined how CXC-chemokine signalling and necrosis 
factor-kappaB (NF-kappaB) activity affected heat-shock protein 90 (Hsp90) 
inhibitor (geldanamycin (GA) and 17-allylamino-demethoxygeldanamycin (17-AAG)) 
cytotoxicity in castrate-resistant prostate cancer (CRPC).
METHODS: Geldanamycin and 17-AAG toxicity, together with the CXCR2 antagonist 
AZ10397767 or NF-kappaB inhibitor BAY11-7082, was assessed by 3-(4, 
5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay in two CRPC 
lines, DU145 and PC3. Flow cytometry quantified apoptotic or necrosis profiles. 
Necrosis factor-kappaB activity was determined by luciferase readouts or 
indirectly by quantitative PCR and ELISA-based determination of CXCL8 
expression.
RESULTS: Geldanamycin and 17-AAG reduced PC3 and DU145 cell viability, although 
PC3 cells were less sensitive. Addition of AZ10397767 increased GA (e.g., PC3 
IC(20): from 1.67+/-0.4 to 0.18+/-0.2 nM) and 17-AAG (PC3 IC(20): 43.7+/-7.8 to 
0.64+/-1.8 nM) potency in PC3 but not DU145 cells. Similarly, BAY11-7082 
increased the potency of 17-AAG in PC3 but not in DU145 cells, correlating with 
the elevated constitutive NF-kappaB activity in PC3 cells. AZ10397767 increased 
17-AAG-induced apoptosis and necrosis and decreased NF-kappaB activity/CXCL8 
expression in 17-AAG-treated PC3 cells.
CONCLUSION: Ansamycin cytotoxicity is enhanced by inhibiting NF-kappaB activity 
and/or CXC-chemokine signalling in CRPC cells. Detecting and/or inhibiting 
NF-kappaB activity may aid the selection and treatment response of CRPC patients 
to Hsp90 inhibitors.