Abstract
BackgroundWe 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.MethodsMouse (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.ResultsSV119, 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 (1 mg/day) in combination with weekly treatment of gemcitabine (1.5 mg/week) for 2 weeks also showed a survival benefit (p = 0.046). Animals tolerated the combination therapy and no gross toxicity was noted in serum biochemistry data or on necropsy.ConclusionSV119 augments tumoricidal activity of paclitaxel and gemcitabine without major side effects. These results highlight the potential utility of the sigma-2 ligand as an adjuvant treatment in pancreas cancer.
Highlights
We have previously reported that the sigma-2 receptor is highly expressed in pancreas cancer
We have demonstrated that sigma-2 receptor specific ligands induce apoptosis in a dose-dependent fashion and that this activity occurs, at least in part, via the intrinsic apoptotic pathway
Sigma-2 ligands have a high affinity for pancreatic adenocarcinoma cell lines compared to normal cell lines We have previously reported that murine (Panc-02) and human (AsPC-1, CFPAC-1, and Panc-1) pancreatic adenocarcinoma cell lines display increased expression of the sigma-2 receptor [13]
Summary
We have previously reported that the sigma-2 receptor is highly expressed in pancreas cancer. We have demonstrated that sigma-2 receptor specific ligands induce apoptosis in a dose-dependent fashion. We examined whether sigma-2 receptor ligands potentiate conventional chemotherapies such as gemcitabine and paclitaxel. The 5-year survival rate is less than 5% [2]. This poor outcome stems from the difficulty in achieving an early diagnosis and the failure of surgery, radiation and chemotherapy. Most patients with pancreas cancer show local recurrence or metastasis within 1 year. The current standard chemotherapeutic, gemcitabine, demonstrates a slight improvement in survival, but these modest results are not satisfactory [4].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
