Abstract 2131: Functional assays to define agonists and antagonists of sigma-2 receptors.

Abstract

Abstract The sigma receptor was originally defined pharmacologically as the specific binding site for a group of compounds named as sigma ligands. The sigma-2 receptor has been identified as a biomarker in proliferating tumors. It regulates cell growth and is an emerging target for cancer diagnosis and therapeutics. Up to date numerous sigma-2 selective ligands have been developed. However, there is no well-established functional assay for defining agonist/antagonist for sigma-2 receptors. Many sigma-2 ligands with diverse structures have been shown to induce cytotoxicity in a variety of cancer cells by triggering caspase-independent and caspase-dependent apoptosis. Therefore, in the current study, we propose to use cell viability and caspase 3 activity, a hallmark of apoptosis, as functional assays to define agonist/antagonist for sigma-2 receptors. Three classes of sigma-2 ligands developed in our laboratory were tested in these two assays in two tumor cell lines: mouse breast cancer cell line EMT6 and human melanoma cell line MDA-MB435. Based on the ratios of the EC50 values of our sigma-2 ligands to the EC50 of siramesine, we categorized the azabicyclononane analogs as agonists (e.g. SV 119) or partial agonists (e.g. WC 26 and SV 95), and benzamide analogs as non-canonical antagonists (e.g. RHM-1) since they do not trigger cell death, and they do not block sigma-2 agonist-induced cell death. SV 95 partially blocked SV 119-induced cytotoxicity. The establishment of functional assays for defining agonist/antagonist will facilitate functional characterization of sigma-2 ligands and sigma-2 receptors. Citation Format: Robert H. Mach, Chenbo Zeng, Justin M. Rothfuss, Jun Zhang, Suwanna Vangveravong, Wenhua Chu, Zhude Tu, Shihong Li. Functional assays to define agonists and antagonists of sigma-2 receptors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2131. doi:10.1158/1538-7445.AM2013-2131