Interleukin 6, a nuclear factor-kappaB target, predicts resistance to docetaxel in hormone-independent prostate cancer and nuclear factor-kappaB inhibition by PS-1145 enhances docetaxel antitumor activity.
OBJECTIVE
To investigate whether nuclear factor kappaB (NF-kappaB)/interleukin 6 (IL-6) was linked to docetaxel response in human prostate cancer cell lines, and whether inhibition of NF-kappaB sensitized tumor cells to docetaxel. We also aimed to correlate IL-6 (as a surrogate marker of NF-kappaB) and docetaxel response in hormone-independent prostate cancer (HIPC) patients.


METHODS
Hormone-dependent (LNCaP) and hormone-independent (PC-3 and DU-145) prostate cancer cell lines were exposed to docetaxel alone or combined with the NF-kappaB inhibitor PS-1145 (an inhibitor of IkappaB kinase-2). Effects of dose, exposure time, and schedule dependence were assessed. Activation of NF-kappaB was assayed by electrophoresis mobility shift assay and luciferase reporter assay, IL-6 levels by ELISA, and cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle and apoptosis were assessed by fluorescence-activated cell sorting analysis. Apoptosis was also measured by detection of cleavage of poly(ADP-ribose) polymerase. In patients with metastatic HIPC receiving docetaxel-based chemotherapy, IL-6 serum levels were assayed before chemotherapy and every 3 to 4 weeks thereafter.


RESULTS
PC-3 and DU-145 cells had higher NF-kappaB activity, secreted more IL-6, and were more resistant to docetaxel than LNCaP cells. NF-kappaB activity was induced by docetaxel. Cotreatment with docetaxel and PS-1145 prevented docetaxel-induced NF-kappaB activation, reduced IL-6 production, and increased docetaxel effects on cell viability in PC-3 and DU-145 cells but not in LNCaP. Synergism with docetaxel and PS-1145, as assayed by median-effect principle, was observed in DU-145 and PC-3. In HIPC patients, pretreatment IL-6 serum levels correlated to prostate-specific antigen (PSA) response: median IL-6 level was 10.8+/-9.5 pg/mL in PSA responders versus 36.7+/-20.8 pg/mL (P=0.006) in nonresponders. A PSA response was also linked to a decline in IL-6 levels during treatment. Median overall survival was 6.8 months in patients with high IL-6 versus 16.6 months in those with low IL-6 (P=0.0007). On multivariate analysis, pretreatment IL-6 (P=0.05) was an independent prognostic factor for time to disease progression and survival.


CONCLUSIONS
Inhibition of NF-kappaB emerges as an attractive strategy to enhance docetaxel response in prostate cancer. The interest of this view is further supported by a significant association between high IL-6 in sera of HIPC patients and decreased response to docetaxel.
Domingo-Domenech
Josep
J
Department of Medical Oncology and Laboratory of Experimental Oncology, Institut Clinic Malalties Hemato-Oncologiques, Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
Oliva
Cristina
C
Rovira
Ana
A
Codony-Servat
Jordi
J
Bosch
Marta
M
Filella
Xavier
X
Montagut
Clara
C
Tapia
Marian
M
Campás
Clara
C
Dang
Lenny
L
Rolfe
Mark
M
Ross
Jeffrey S
JS
Gascon
Pere
P
Albanell
Joan
J
Mellado
Begoña
B
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy; D002470:Cell Survival; D018450:Disease Progression; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004357:Drug Synergism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D008198:Lymph Nodes; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000188:drug therapy; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D013223:Statistics as Topic; D016019:Survival Analysis; D043823:Taxoids / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D006575:Heterocyclic Compounds, 3-Ring; D015850:Interleukin-6; D016328:NF-kappa B; C456319:PS1145; D011725:Pyridines; D043823:Taxoids; D000077143:Docetaxel; D017430:Prostate-Specific Antigen