Effects of namodenoson on pancreatic carcinoma: Preclinical evidence.

Abstract

e15134 Background: Namodenoson, an A3 adenosine receptor (A3AR) agonist, is currently in a phase 3 trial for the treatment of advanced liver cancer. The mechanism of action of namodenoson involves de-regulation of the Wnt and NF-κB signaling pathways, followed by an increase in pro-apoptotic proteins and Fas-ligand, resulting in tumor growth inhibition. As the Wnt signaling pathway is also highly implicated in pancreatic carcinogenesis, we examined the anti-growth effect of namodenoson on pancreatic carcinoma cell lines and investigated the molecular mechanism involved. Methods: BxPC-3 human pancreatic carcinoma cells were cultured in the presence and absence of 0.01, 0.1, and 1 nM namodenoson. A combined treatment of namodenoson (0.1 nM) and gemcitabine (0.2 µM) was also studied. 3[H]-thymidine proliferation and MTT assays were used to monitor cell growth, and Western blot analyses were performed to identify the involved regulatory cell growth proteins. Results: Results of the 3[H]-thymidine proliferation assays demonstrated significant dose-dependent inhibition of the growth of BxPC-3 cells with namodenoson (1 nM: 67.4% ± 1.7%, p < 0.001; 0.1 nM: 53.7% ± 6.3%, p < 0.05; 0.01 nM: 27.9 % ± 2.3%, p < 0.005). The MTT results revealed that a combined treatment with namodenoson plus gemcitabine had an additive inhibitory effect (namodenoson: 48.6% ± 1.4%; gemcitabine: 44.4% ± 0.7%; namodenoson plus gemcitabine: 65.4% ± 1.4%; p < 0.001 for all). Western blot analyses showed that namodenoson treatment was associated with downregulation of the Wnt pathway regulatory proteins including p-Akt, NF- κB, GSK-3β, and β-catenin. Conclusions: Our findings showed that nanomolar concentrations of namodenoson inhibit the growth of pancreatic carcinoma via A3AR activation and de-regulation of the Wnt/β-catenin pathway, both as a monotherapy and in combination with gemcitabine. Thus, these results support a potential role for namodenoson in treating pancreatic cancer, thereby opening a novel therapeutic opportunity for this disease.