TY - JOUR
T1 - The novel sigma-2 receptor ligand SW43 stabilizes pancreas cancer progression in combination with gemcitabine
AU - Hornick, John R.
AU - Xu, Jinbin
AU - Vangveravong, Suwanna
AU - Tu, Zhude
AU - Mitchem, Jonathan B.
AU - Spitzer, Dirk
AU - Goedegebuure, Peter
AU - Mach, Robert H.
AU - Hawkins, William G.
N1 - Funding Information:
This study was supported by grants from the American Cancer Society (MRSG-08-019-01CDD, W.G. Hawkins), Veterans Affairs Merit Grant (1136919, W.G. Hawkins), National Institutes of Health T32 Training Grant (5T32CA009621-22, J.R. Hornick), and the National Institutes of Health (CA102869, R.H. Mach). This work was presented in part at the Annual Meeting of the Society for Surgical Oncology, St. Louis, MO, 2010. The authors would like to thank Suellen Greco, DVM DACLAM, from the Division of Comparative Medicine for review and selection of pathologic specimens; Jean Zhang from the Division of Biostatistics for statistical consultation; and Stacey Plambeck-Seuss for technical assistance.
PY - 2010/11/22
Y1 - 2010/11/22
N2 - Background: Sigma-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.Results: The 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.Conclusions: This 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.
AB - Background: Sigma-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.Results: The 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.Conclusions: This 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.
UR - http://www.scopus.com/inward/record.url?scp=78549265187&partnerID=8YFLogxK
U2 - 10.1186/1476-4598-9-298
DO - 10.1186/1476-4598-9-298
M3 - Article
C2 - 21092190
AN - SCOPUS:78549265187
SN - 1476-4598
VL - 9
JO - Molecular Cancer
JF - Molecular Cancer
M1 - 298
ER -