Abstract
BackgroundResistance to modern adjuvant treatment is in part due to the failure of programmed cell death. Therefore the molecules that execute the apoptotic program are potential targets for the development of anti-cancer therapeutics. The sigma-2 receptor has been found to be over-expressed in some types of malignant tumors, and, recently, small molecule ligands to the sigma-2 receptor were found to induce cancer cell apoptosis.ResultsThe sigma-2 receptor was expressed at high levels in both human and murine pancreas cancer cell lines, with minimal or limited expression in normal tissues, including: brain, kidney, liver, lung, pancreas and spleen. Micro-PET imaging was used to demonstrate that the sigma-2 receptor was preferentially expressed in tumor as opposed to normal tissues in pancreas tumor allograft-bearing mice. Two structurally distinct sigma-2 receptor ligands, SV119 and WC26, were found to induce apoptosis to mice and human pancreatic cancer cells in vitro and in vivo. Sigma-2 receptor ligands induced apoptosis in a dose dependent fashion in all pancreatic cell lines tested. At the highest dose tested (10 μM), all sigma-2 receptor ligands induced 10–20% apoptosis in all pancreatic cancer cell lines tested (p < 0.05). In pancreas tumor allograft-bearing mice, a single bolus dose of WC26 caused approximately 50% apoptosis in the tumor compared to no appreciable apoptosis in tumor-bearing, vehicle-injected control animals (p < 0.0001). WC26 significantly slowed tumor growth after a 5 day treatment compared to vehicle-injected control animals (p < 0.0001) and blood chemistry panels suggested that there is minimal peripheral toxicity.ConclusionWe demonstrate a novel therapeutic strategy that induces a significant increase in pancreas cancer cell death. This strategy highlights a new potential target for the treatment of pancreas cancer, which has little in the way of effective treatments.
Highlights
Resistance to modern adjuvant treatment is in part due to the failure of programmed cell death
Pharmacologic studies suggest that the sigma 2 ligand binding site is well conserved between rodents and primates, and we have demonstrated that sigma 2 receptor-specific ligands induce apoptosis in both mouse and human pancreas adenocarcinoma cell lines
Our results show that inhibition of the executioner caspases abrogates WC26induced apoptosis in pancreas adenocarcinoma cell lines, suggesting that sigma 2 receptor-specific ligand-induced apoptosis may be cell type and/or ligand specific
Summary
Resistance to modern adjuvant treatment is in part due to the failure of programmed cell death. Pancreas cancer is the fourth most common cause of cancer-related mortality in the United States[1]. There were an estimated 37,000 deaths attributable to this disease in the United States in 2006[1]. The five-year survival for patients diagnosed with pancreas cancer is only 4%. Poor outcome is the result of difficulty in achieving early diagnosis and failure of modern treatments including surgery, radiation and chemotherapy. Chemotherapy and radiation therapy for pancreatic cancer is palliative. For localized disease surgery remains the single most effective therapy, even with complete surgical resection, the prognosis remains dismal and the majority of patients recur with systemic metastases. There is a critical need for an effective systemic therapy utilizing a new strategy
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