Abstract 3814: Combination of selective modular of the glucocorticoid receptor (SEGRA) with proteasome inhibitors as a novel strategy for chemotherapy of hematologic malignancies

Abstract

Abstract Glucocorticoids are widely used for the treatment of hematological malignancies; however chronic treatment with steroids results in numerous adverse effects. Glucocorticoid receptor (GR) regulates gene expression via transactivation that requires GR homodimer binding to gene promoters; and transrepression mediated via negative interaction between GR and other transcription factors. GR transactivation is linked to metabolic side effects, while GR transrepression underlies glucocorticoid therapeutic action. One of the novel GR modulators is 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium-chloride also called CpdA. CpdA is a synthetic analogue of a aziridine precursor isolated from the Namibian shrub Salsola tuberculatiformis Botschantzev. Using representative human T cell (CEM) and B cell (NCEB) lymphoma cell lines expressing functional GR, and their counterparts with blocked GR expression, we showed that CpdA indeed acted as dissociated GR ligand, and inhibited growth and survival of these cells via GR. Sensitivity to therapeutic effects of GCs directly depends on the amount of functional GR. The 26S protesome controls GR protein stability, and is responsible for desensitization to GCs via hormone-induced GR degradation and following development of glucocorticoid resistance in patients. Thus, the use of proteasome inhibitors represents a pharmacological approach to prevent GR down-regulation and to elevate the level of GR in cells. Proteasome inhibitor Bortezomib (BZ) was approved by FDA for the treatment of patients with multiple myeloma and mantle cell lymphoma. Since proteasome inhibitors stabilize GR, we hypothesized that BZ will augment CpdA effects as a selective GR modulator and enhance its chemotherapeutic activity. We showed that pretreatment of CEM and NCEB cells with proteasome inhibitor Bortezomib resulted in GR accumulation, and enhanced CpdA ligand properties further shifting GR activity towards transrepression evaluated by inhibiton of NF-kB and AP-1 factors. We also revealed remarkable GR-dependent synergy between CpdA and BZ in suppressing growth and survival of T and B lymphoma cells. Overall, our data provide the rationale for novel GR-based therapy for lymphoma and leukemia based on the combination of non-steroidal GR modulators with proteasome inhibitors. 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 3814. doi:1538-7445.AM2012-3814