Data from Effects of Siltuximab on the IL-6–Induced Signaling Pathway in Ovarian Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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 <i>in vivo</i>.</p><p><b>Results:</b> 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-X<sub>L</sub>, 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 <i>in vitro</i>, but combination therapy with siltuximab did not have a significant effect on paclitaxel resistant tumor growth <i>in vivo</i>.</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 16(23); 5759–69. ©2010 AACR.</i></p></div>