The novel sigma-2 receptor ligand SW43 stabilizes pancreas cancer progression in combination with gemcitabine

Abstract

BackgroundSigma-2 receptors are over-expressed in proliferating cancer cells, making an attractive target for the targeted treatment of pancreatic cancer. In this study, we investigated the role of the novel sigma-2 receptor ligand SW43 to induce apoptosis and augment standard chemotherapy.ResultsThe binding affinity for sigma-2 ligands is high in pancreas cancer, and they induce apoptosis with a rank order of SV119 < SW43 < SRM in vitro. Combining these compounds with gemcitabine further increased apoptosis and decreased viability. Our in vivo model showed that sigma-2 ligand treatment decreased tumor volume to the same extent as gemcitabine. However, SW43 combination treatment with gemcitabine was superior to the other compounds and resulted in stabilization of tumor volume during treatment, with minimal toxicities.ConclusionsThis study shows that the sigma-2 ligand SW43 has the greatest capacity to augment gemcitabine in a pre-clinical model of pancreas cancer and has provided us with the rationale to move this compound forward with clinical investigations for patients with pancreatic cancer.

Elements in support of the ‘non-identity’ of the PGRMC1 protein with the σ2 receptor

“…3) which were previously reported to exert σ 2 mediated antiproliferative action. Among these compounds, siramesine and PB28 are two reference σ 2 agonists whose antiproliferative σ 2 mediated effect has been shown in diverse tumor cell lines as well as in vivo tumor models (Zeng et al, 2012;Hornick et al, 2012Hornick et al, , 2010Niso et al, 2013;Abate et al, 2011Abate et al, , 2012bBerardi et al, 2009). Six concentrations of the compounds were used (from 1 μM to 100 μM) to investigate their antiproliferative action in MCF7, MCF7_SH and MCF7_PGRMC1 cell lines (Fig.…”

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

“…Other receptors that may be present in sufficient quantities on cancer cells to be useful for targeted drug delivery include somatostatin receptor 2 (SSTR2) [56][57][58] , cholecystokinin type B receptor (CCKBR) [59][60][61] , bombesin receptor [62][63][64] , and sigma non-opioid intracellular receptor 1 (SIGMAR1) and SIGMAR2 (REFS. [65][66][67][68][69]. Moreover, several cell-adhesion proteins 70 , such as intercellular adhesion molecule 1 (ICAM1; also known as CD54) [71][72][73] , leukocyte function-associated antigen 1 (LFA1; also known as ITGB2) 74 and CD24 (REF.…”

Deconstruction of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety to separate P-glycoprotein (P-gp) activity from σ2 receptor affinity in mixed P-gp/σ2 receptor agents

“…Further interest in the σ 2 receptor has been generated by the evidence that its activation through specific putative σ 2 agents leads to tumor cell death. A few classes of σ 2 ligands endowed with antiproliferative activity have been developed [14] and some encouraging results from in vivo assays are giving impulse to further studies [15][16][17][18]. In our continuous effort to contribute to the σ 2 -receptor research, we conducted several Structure Affinity Relationship studies (SAfiR) on diverse classes of σ receptor ligands [19][20][21][22][23].…”