Sigma-2 receptor ligands potentiate conventional chemotherapies and improve survival in models of pancreatic adenocarcin
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BioMed Central
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Sigma-2 receptor ligands potentiate conventional chemotherapies and improve survival in models of pancreatic adenocarcinoma Hiroyuki Kashiwagi1, Jonathan E McDunn2, Peter O Simon Jr1, Peter S Goedegebuure1,3, Suwanna Vangveravong4, Katherine Chang2, Richard S Hotchkiss2, Robert H Mach4 and William G Hawkins*1,3 Address: 1Department of Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8109, St. Louis, MO 63110, USA, 2Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA, 3Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8109, St. Louis, MO 63110, USA and 4Department of Radiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA Email: Hiroyuki Kashiwagi - [email protected]; Jonathan E McDunn - [email protected]; Peter O Simon - [email protected]; Peter S Goedegebuure - [email protected]; Suwanna Vangveravong - [email protected]; Katherine Chang - [email protected]; Richard S Hotchkiss - [email protected]; Robert H Mach - [email protected]; William G Hawkins* - [email protected] * Corresponding author
Published: 26 March 2009 Journal of Translational Medicine 2009, 7:24
doi:10.1186/1479-5876-7-24
Received: 14 November 2008 Accepted: 26 March 2009
This article is available from: http://www.translational-medicine.com/content/7/1/24 © 2009 Kashiwagi et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background: We have previously reported that the sigma-2 receptor is highly expressed in pancreas cancer. Furthermore, we have demonstrated that sigma-2 receptor specific ligands induce apoptosis in a dose-dependent fashion. Here, we examined whether sigma-2 receptor ligands potentiate conventional chemotherapies such as gemcitabine and paclitaxel. Methods: Mouse (Panc-02) and human (CFPAC-1, Panc-1, AsPC-1) pancreas cancer cell lines were used in this study. Apoptosis was determined by FACS or immunohistochemical analysis after TUNEL and Caspase-3 staining. Combination therapy with the sigma-2 ligand SV119 and the conventional chemotherapies gemcitabine and paclitaxel was evaluated in an allogenic animal model of pancreas cancer. Results: SV119, gemcitabine, and paclitaxel induced apoptosis in a dose-dependent fashion in all pancreas cancer cell lines tested. Combinations demonstrated increases in apoptosis. Mice were treated with SV119 (1 mg/day) which was administered in combination with paclitaxel (300 μg/day) over 7 days to mice with established tumors. A survival benefit was observed with combination therapy (p = 0.0002). Every other day treatment of SV119
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