Abstract 2777: Suppression of multiple myeloma via non-canonical inhibition of NF-κB

Abstract

Abstract Multiple myeloma is a deadly disease for which treatment has significantly improved with the introduction of the proteasome inhibitor bortezomib. The mechanism of cell death invoked by proteasome inhibition is unknown, but likely involves multiple pathways, including downregulation of NF-κB activity, stabilization of pro-apoptotic factors, and induction of the unfolded protein response, which may be especially critical for apoptosis of B-cell tumors. However, most patients ultimately experience disease relapse, and novel treatments are clearly necessary. We have developed a novel class of proteasome inhibitors called trans-imidazolines that target the proteasome differently from bortezomib and exhibit substantial anti-inflammatory properties when tested in mouse models of rheumatoid arthritis. The purpose of the current studies was to determine the efficacy of these small molecule anti-inflammatory agents for inhibition of multiple myeloma proliferation and survival. For these studies, trans-imidazoline efficacy was initially determined in vitro against a panel of multiple myeloma cell lines with effects on apoptotic induction determined by fluorescent activated cell sorting analysis. Subsequent studies were expanded to examine multiple myeloma tumor growth in mouse xenograft assays. Component levels of the NF-κB pathway were examined by Western blot analyses and immunofluorescent staining after challenge with exogenous cytokines. The biochemical mechanism of trans-imidazoline function was further explored in vitro using proteasome assays of fluorescently tagged peptide substrates. Our data indicates that trans-imidazolines impede IαBβ turnover in response to TNFα treatment and are consequently effective inhibitors of NF-κB activity for transcriptional activation. As NF-κB mediates key pro-survival roles in multiple myeloma, these compounds were found to induce apoptosis in multiple myeloma cells as rapidly as bortezomib, and demonstrated impressive inhibition of RPMI-8226 tumor growth in mice. Importantly, trans-imidazolines are equally effective inhibitors of bortezomib-resistant tumor cell proliferation. Consistent with these observations, we found that trans-imidazolines inhibit proteasome activity via a non-competitive mechanism that is distinct from the active site competitive inhibition mechanism displayed by bortezomib. As acquired resistance to bortezomib often occurs via increased expression of its proteasome target, trans-imidazolines thus offer an alternative treatment option for recurrent disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2777. doi:1538-7445.AM2012-2777