Effects of Siltuximab on the IL-6–Induced Signaling Pathway in Ovarian Cancer
- 1 December 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 16 (23), 5759-5769
- https://doi.org/10.1158/1078-0432.ccr-10-1095
Abstract
Purpose: To explore potential therapeutic strategies for interrupting the interleukin-6 (IL-6) signaling pathway, we measured IL-6 expression in ovarian cancer tissues, and evaluated the effects of a monoclonal anti-IL-6 antibody; siltuximab (CNTO 328), on levels of IL-6–induced Stat3 phosphorylation, Stat3 nuclear translocation, and Stat3 downstream antiapoptotic genes. We then looked for enhancing paclitaxel sensitivity in multidrug-resistant ovarian cancer cell lines. Experimental Design: Expressions of IL-6 in ovarian cancer patient specimens were assessed by immunohistochemistry. Effects of siltuximab on IL-6–induced activation of Stat3 in an ovarian cancer cell line were determined by Western blot and real-time analysis of Stat3 nucleocytoplasmic translocation. Influence of combination of siltuximab and paclitaxel on tumor growth was evaluated in a xenograft mouse mode in vivo. Results: Metastatic and drug-resistant recurrent tumors have significantly higher IL-6 expression when compared with the matched primary tumors. Siltuximab specifically suppressed IL-6–induced Stat3 phosphorylation and Stat3 nuclear translocation. Treatment with siltuximab significantly decreased the levels of Stat3 downstream proteins such as MCL-1, Bcl-XL, and survivin. Treatment with siltuximab reduced expression of multiple IL-6–induced genes in these cell lines. Furthermore, siltuximab increased the cytotoxic effects of paclitaxel in a paclitaxel resistant ovarian cancer cell line in vitro, but combination therapy with siltuximab did not have a significant effect on paclitaxel resistant tumor growth in vivo. Conclusions: These results show that siltuximab effectively block the IL-6 signaling pathways and IL-6–induced gene expression. Blockage of IL-6 signaling may provide benefits for the treatment of ovarian cancer. Clin Cancer Res; 16(23); 5759–69. ©2010 AACR.Keywords
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