Abstract
Purpose: Interleukin-6 (IL-6) is a pleiotropic, antiapoptotic cytokine that is overexpressed in ovarian cancer. To explore potential therapeutic strategies for interrupting the IL-6 signaling through this pathway, we assessed IL-6 expression in ovarian cancer tissues, and the monoclonal antibody siltuximab’s ability (CNTO 328) to inhibit IL-6 induced Stat3 phosphorylation, Stat3 nuclear translocation, and Stat3 downstream antiapoptotic genes, thereby enhancing paclitaxel sensitivity in multidrug resistant ovarian cancer cell lines. 河南省人民医院妇科郭玉琪
Experimental Design: Expressions of IL-6 in ovarian cancer patient specimens were assessed by immunohistochemistry. Effect of siltuximab on IL-6 induced activation of Stat3 in ovarian cancer cell line was 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: The metastatic and drug-resistant recurrent tumors have significantly greater IL-6 expression as compared to 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 L and survivin. Examination of the effects of siltuximab on the IL-6 induced gene expression revealed that a large number of genes have altered expression levels in IL-6 treated SKOV-3 and Caov-3 cell lines when compared to the parental cell lines. 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 , and combination therapy with siltuximab did not have a significant effect on paclitaxel resistant tumor growth in vivo .
Conclusions: These results demonstrated that siltuximab effectively block the IL-6 signaling pathway s and IL-6-induced gene expression. Blockage of IL-6 signaling may provide benefits for the treatment of ovarian cancer.
