Effects of siltuximab on the IL-6-induced signaling pathway in ovarian cancer

Clin Cancer Res. 2010 Dec 1;16(23):5759-69. doi: 10.1158/1078-0432.CCR-10-1095. Epub 2010 Aug 10.

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-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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Carcinoma / drug therapy*
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Carcinoma / pathology*
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Interleukin-6 / pharmacology*
  • Mice
  • Mice, Nude
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Paclitaxel / administration & dosage
  • STAT3 Transcription Factor / metabolism
  • STAT3 Transcription Factor / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Validation Studies as Topic
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • Interleukin-6
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Paclitaxel
  • siltuximab