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Interleukin 6, a Nuclear Factor-B Target, Predicts Resistance to Docetaxel in Hormone-Independent Prostate Cancer and Nuclear Factor-B Inhibition by PS-1145 Enhances Docetaxel Antitumor Activity

Authors' Affiliations: ¹ Department of Medical Oncology and Laboratory of Experimental Oncology, Institut Clinic Malalties Hemato-Oncologiques, and ² Department of Biochemistry, Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain; ³ Medical Oncology Department and Experimental Therapeutics Research Unit, Hospital del Mar, Instituto Municipal de Investigación Médica, Instituto Municipal de Asistencia Sanitaria, Barcelona, Spain; ⁴ Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts; and ⁵ Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York

Requests for reprints: Begoña Mellado, Department of Medical Oncology, Institut Clinic Malalties Hemato-Oncologiques, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic, c/Villarroel 170, 08036 Barcelona, Spain. Phone/Fax: 34-93-2275402; E-mail: bmellado{at}clinic.ub.es.

Purpose: To investigate whether nuclear factor B (NF-B)/interleukin 6 (IL-6) was linked to docetaxel response in human prostate cancer cell lines, and whether inhibition of NF-B sensitized tumor cells to docetaxel. We also aimed to correlate IL-6 (as a surrogate marker of NF-B) and docetaxel response in hormone-independent prostate cancer (HIPC) patients.

Experimental Design: 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-B inhibitor PS-1145 (an inhibitor of IB kinase-2). Effects of dose, exposure time, and schedule dependence were assessed. Activation of NF-B 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-B activity, secreted more IL-6, and were more resistant to docetaxel than LNCaP cells. NF-B activity was induced by docetaxel. Cotreatment with docetaxel and PS-1145 prevented docetaxel-induced NF-B 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-B 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.

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