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.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ovarian cancer is the most lethal gynecological malignancy, with few effective treatment options in most cases. Therefore, understanding the biology of ovarian cancer remains an important area of research in order to improve clinical outcomes. Cytokine receptor signaling through the Janus kinase-Signal transducer and activator of transcription (JAK-STAT) pathway is an essential component of normal development and homeostasis. However, numerous studies have implicated perturbation of this pathway in a range of cancers. In particular, members of the IL-6R family acting via the downstream STAT3 transcription factor play an important role in a number of solid tumors - including ovarian cancer - by altering the expression of target genes that impact on key phenotypes. This has led to the development of specific inhibitors of this pathway which are being used in combination with standard chemotherapeutic agents. This review focuses on the role of IL-6R family members in the etiology of epithelial ovarian cancer, and the application of therapies specifically targeting IL-6R signaling in this disease setting.
    Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 01/2014; · 7.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The anti-interleukin-6 (IL-6) chimeric monoclonal antibody siltuximab is the first drug to be approved for the treatment of multicentric Castleman's disease (MCD) in the US and European union (EU), having gained approval under the FDA priority review program in the US and from an accelerated assessment and recommendation by the Committee for Medicinal Products for Human Use (CHMP) in the EU. Development of the drug is continuing in smoldering multiple myeloma. This article summarizes the milestones in the development of siltuximab leading to this first approval for MCD.
    Drugs. 06/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: IL-6 signaling plays a prominent role in tumorigenesis and metastasis. In this review we discuss the recent evidence describing the tumor intrinsic and extrinsic functions of this signaling pathway. Although blockade of this pathway in pre-clinical models leads to a reduction in tumor growth and metastasis, its clinical success is less evident. Thus, identifying the features of tumors/patients that predict response to anti-IL6 therapy are needed.
    Seminars in Immunology 01/2014; · 6.12 Impact Factor

Full-text (2 Sources)

Available from
May 31, 2014