Effects of Siltuximab on the IL6 Induced Signaling Pathway in Ovarian Cancer

Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA 02114, USA.
Clinical Cancer Research (Impact Factor: 8.19). 12/2010; 16(6). DOI: 10.1158/1078-0432.CCR-10-1095
Source: PubMed

ABSTRACT 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.
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.
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(L), 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.
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.

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Available from: Michiro Susa, Jul 11, 2015
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    • "One such anti-IL-6 monoclonal antibody is Siltuximab (CNTO 328). The safety and efficacy of Situximab has been demonstrated in preclinical studies and phase I/II clinical trials of diverse human pathologies and malignancies including Castleman's disease (van Rhee et al., 2010), multiple myeloma (Hunsucker et al., 2011; Voorhees et al., 2007), prostate cancer (Cavarretta et al., 2007; Cavarretta et al., 2008; Dorff et al., 2010; Karkera et al., 2011), renal cell carcinoma (Puchalski et al., 2010; Rossi et al., 2010), non-small cell lung cancer (Song et al., 2010), and ovarian cancer (Guo et al., 2010). Furthermore, IL-6R can be targeted with tocilizumab, an anti-IL-6R monoclonal antibody that has shown promising results in IL-6- driven autoimmune diseases (Tanaka et al., 2011) and was recently approved by the FDA for the treatment of rheumatoid arthritis. "
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