We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Inhibition of constitutive and cxc-chemokine-induced NF-kappaB activity potentiates ansamycin-based HSP90-inhibitor cytotoxicity in castrate-resistant prostate cancer cells.
- Authors
Seaton, A.; Maxwell, P. J.; Hill, A.; Gallagher, R.; Pettigrew, J.; Wilson, R. H.; Waugh, D. J. J.
- Abstract
<bold>Background: </bold>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).<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.
- Subjects
PROSTATE cancer; CANCER cells; CHEMOKINES; CANCER patients; ENZYME-linked immunosorbent assay; CELL death; PROTEINS; INTERLEUKINS; RESEARCH; BENZOQUINONES; RESEARCH methodology; ANTI-infective agents; CELL receptors; ORGANIC compounds; APOPTOSIS; CELL physiology; MEDICAL cooperation; EVALUATION research; CELLULAR signal transduction; COMPARATIVE studies; DNA-binding proteins; SULFONES; CASTRATION; CELL lines; AMIDES; PROSTATE tumors; NECROSIS; PHARMACODYNAMICS; CHEMICAL inhibitors
- Publication
British Journal of Cancer, 2009, Vol 101, Issue 9, p1620
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/sj.bjc.6605356