Inhibition of Interleukin-6 with CNTO328, an Anti-Interleukin-6 Monoclonal Antibody, Inhibits Conversion of Androgen-Dependent Prostate Cancer to an Androgen-Independent Phenotype in Orchiectomized Mice

Abstract

Initially, prostate cancer is androgen dependent. However, most cases progress to an androgen-independent state through unknown mechanisms. Interleukin-6 (IL-6) has been associated with prostate cancer progression including activation of the androgen receptor (AR). To determine if IL-6 plays a role in the conversion of prostate cancer from androgen dependent to androgen independent, we established androgen-dependent LuCaP 35 human prostate cancer xenografts in nude mice, castrated the mice, and blocked IL-6 activity using a neutralizing antibody (CNT0328) for a period of 18 weeks. IL-6 inhibition increased survival of mice and inhibited tumor growth, as reflected by decreased tumor volume and prostatespecific antigen levels, compared with that in mice receiving isotype control antibody. To test the effect of IL-6 inhibition on the conversion from androgen dependent to androgen independent, tumor cells from the treated mice were assessed for their androgen dependence both in vitro and by implanting them into sham-operated or orchiectomized mice. Tumor cells derived from the isotype-treated animals converted to androgen-independent state, whereas tumor cells from the anti-IL-6 antibody-treated mice were still androgen dependent in vitro and in vivo. Although there was no difference in AR levels between the androgen-independent and androgen-dependent tumors, IL-6 inhibition promoted both apoptosis and inhibited cell proliferation in tumors and blocked the orchiectomyinduced expression of histone acetylases, p300 and CBP, which are AR cofactors. These data show that IL-6 contributes to the development of androgen independence in prostate cancer and suggest that it mediates this effect, in part, through modulation of p300 and CBP. (Cancer Res 2006; 66(6): 3087-95)

The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1

“…CNTO 328 was able to render LNCaP-IL-6 þ cells more sensitive to apoptosis. Taken together with recent data by Wallner et al (2006) who showed effects of CNTO 328 in the LuCaP 35 xenograft, these results support the concept of anti-IL-6 therapy in human prostate cancer.…”

Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer

“…IL-6 has been associated with progression from hormone-sensitive to hormone-insensitive disease in animal models via interaction with AR cofactors (Wallner et al, 2006). One possible mode by which IL-6 may influence progression of prostate cancer to the hormone-refractory state is by activating the IL-6 receptor/JAK1/ STAT3 pathway, resulting in differentiation and inhibition of apoptosis (Spiotto and Chung, 2000a;Smith et al, 2001).…”

“…Cytoplasmic expression of IL-6 receptor and pSTAT3 Tyr705 are associated with reduced time to biochemical relapse and reduced time to death from hormone relapse respectively, therefore, supporting the strategy for targeting this pathway in hormone-refractory prostate cancer treatments. A recent report demonstrates that this pathway can be targeted and successfully inhibited in other disease using a humanised monoclonal antibody that targets the IL-6 receptor (in a similar to which herceptin targets HER2 (Jia et al, 2004;Nakahara and Nishimoto, 2006;Nishimoto and Kishimoto, 2006) and this approach has proved successful in prostate cancer animal models (Wallner et al, 2006). Use of this drug (tocilixumab) in phase II clinical trials for rheumatoid arthritis has proved the clinical benefit of IL-6 blockade and we suggest that such a strategy should be applied to hormonerefractory (Nishimoto and Kishimoto, 2006).…”

The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth

“…In addition, IL-6 has been associated with progression from hormone-sensitive to hormone-insensitive disease in animal models via interaction with androgen receptor (AR) cofactors (26). Basically, IL-6 binds to its cognate a-chain receptor (IL-6 receptor) with low affinity, and then the complex binds to the signal-transducing molecule gp130 (h-subunit) to form a high-affinity complex (27).…”