Selective sigma-2 ligands preferentially bind to pancreatic adenocarcinomas: applications in diagnostic imaging and therapy. Mol Cancer 2007 Jul 15;6:48
Date
07/17/2007Pubmed ID
17631687Pubmed Central ID
PMC1939854DOI
10.1186/1476-4598-6-48Scopus ID
2-s2.0-34547773199 (requires institutional sign-in at Scopus site) 111 CitationsAbstract
BACKGROUND: Resistance 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.
RESULTS: The 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 muM), 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.
CONCLUSION: We 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.
Author List
Kashiwagi H, McDunn JE, Simon PO Jr, Goedegebuure PS, Xu J, Jones L, Chang K, Johnston F, Trinkaus K, Hotchkiss RS, Mach RH, Hawkins WGMESH terms used to index this publication - Major topics in bold
AdenocarcinomaAnimals
Antineoplastic Agents
Apoptosis
Azabicyclo Compounds
Binding, Competitive
Brain
Carbamates
Caspase 3
Cell Line, Tumor
Cell Survival
Dose-Response Relationship, Drug
Female
Humans
Kidney
Ligands
Lung
Mice
Mice, Inbred C57BL
Neoplasms, Experimental
Pancreatic Neoplasms
Positron-Emission Tomography
Radioligand Assay
Receptors, sigma
Signal Transduction
Survival Analysis
Tritium