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.
Highlights
Sigma-2 receptors are over-expressed in proliferating cancer cells, making an attractive target for the targeted treatment of pancreatic cancer
The sigma-2 specific ligands SRM and SV119 and sigma-1 specific ligand pentazocine were compared to the novel sigma-2 ligand SW43 in characterization of the pharmacological binding profile to sigma-2 receptors in Panc02 tumor membrane homogenates
The range of IC50 values was 50-106 μM for SV119, 21-56 μM for SW43, and 11-36 μM for SRM
Summary
Sigma-2 receptors are over-expressed in proliferating cancer cells, making an attractive target for the targeted treatment of pancreatic cancer. We investigated the role of the novel sigma-2 receptor ligand SW43 to induce apoptosis and augment standard chemotherapy. Sigma-2 ligands have been investigated for their therapeutic role in the treatment of cancers, and we have previously shown sigma-2 receptor overexpression in Panc tumor bearing C57BL/6 mice and an increased survival in this model by treatment with novel sigma-2 ligands [8,9]. These compounds offer promising potential as novel therapeutics for the treatment of solid tumors, including pancreatic cancer. Multiple compounds with higher specificity to sigma-2 receptors have been used for binding studies [125I]-ISO2 Competition
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