Selective sigma-2 ligands preferentially bind to pancreatic adenocarcinomas: applications in diagnostic imaging and therapy
<p>Abstract</p> <p>Background</p> <p>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 sig...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2007-07-01
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| Series: | Molecular Cancer |
| Online Access: | http://www.molecular-cancer.com/content/6/1/48 |
| _version_ | 1811310490046955520 |
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| author | Johnston Fabian Chang Katherine Jones Lynne Xu Jinbin Goedegebuure Peter S Simon Peter O McDunn Jonathan E Kashiwagi Hiroyuki Trinkaus Kathryn Hotchkiss Richard S Mach Robert H Hawkins William G |
| author_facet | Johnston Fabian Chang Katherine Jones Lynne Xu Jinbin Goedegebuure Peter S Simon Peter O McDunn Jonathan E Kashiwagi Hiroyuki Trinkaus Kathryn Hotchkiss Richard S Mach Robert H Hawkins William G |
| author_sort | Johnston Fabian |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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 <it>in vitro </it>and <it>in vivo</it>. 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.</p> <p>Conclusion</p> <p>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.</p> |
| first_indexed | 2024-04-13T09:59:42Z |
| format | Article |
| id | doaj.art-9bac540b83e4481da9be07b3d8d7bcb7 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-04-13T09:59:42Z |
| publishDate | 2007-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-9bac540b83e4481da9be07b3d8d7bcb72022-12-22T02:51:16ZengBMCMolecular Cancer1476-45982007-07-01614810.1186/1476-4598-6-48Selective sigma-2 ligands preferentially bind to pancreatic adenocarcinomas: applications in diagnostic imaging and therapyJohnston FabianChang KatherineJones LynneXu JinbinGoedegebuure Peter SSimon Peter OMcDunn Jonathan EKashiwagi HiroyukiTrinkaus KathrynHotchkiss Richard SMach Robert HHawkins William G<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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 <it>in vitro </it>and <it>in vivo</it>. 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.</p> <p>Conclusion</p> <p>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.</p>http://www.molecular-cancer.com/content/6/1/48 |
| spellingShingle | Johnston Fabian Chang Katherine Jones Lynne Xu Jinbin Goedegebuure Peter S Simon Peter O McDunn Jonathan E Kashiwagi Hiroyuki Trinkaus Kathryn Hotchkiss Richard S Mach Robert H Hawkins William G Selective sigma-2 ligands preferentially bind to pancreatic adenocarcinomas: applications in diagnostic imaging and therapy Molecular Cancer |
| title | Selective sigma-2 ligands preferentially bind to pancreatic adenocarcinomas: applications in diagnostic imaging and therapy |
| title_full | Selective sigma-2 ligands preferentially bind to pancreatic adenocarcinomas: applications in diagnostic imaging and therapy |
| title_fullStr | Selective sigma-2 ligands preferentially bind to pancreatic adenocarcinomas: applications in diagnostic imaging and therapy |
| title_full_unstemmed | Selective sigma-2 ligands preferentially bind to pancreatic adenocarcinomas: applications in diagnostic imaging and therapy |
| title_short | Selective sigma-2 ligands preferentially bind to pancreatic adenocarcinomas: applications in diagnostic imaging and therapy |
| title_sort | selective sigma 2 ligands preferentially bind to pancreatic adenocarcinomas applications in diagnostic imaging and therapy |
| url | http://www.molecular-cancer.com/content/6/1/48 |
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