Over the last 30 years, little improvement has been made to the 5 year survival rate of pancreatic cancer (PanCA) patients. While survival has increase by 2% over the last several years, the current rate is still less than 8%. This depressing fact demonstrates the importance of developing or improving therapies to more effectively manage this disease. Along these lines, published studies from our laboratory demonstrated the anti-tumorigenic potential of the cork tree bark extract, Nexrutine® (Nx). Nx suppressed growth of pancreatic cancer cells through downregulation of STAT3/NF-κB activation. Subsequent biochemical and molecular investigations revealed palmatine (PMT) (i) as an active constituent of Nx able to suppress the growth of pancreatic cancer cells; (ii) synergizes with gemcitabine (GEM); and (iii) downregulates GLI1, COL1A1 and Survivin. Despite such promising in vitro observations however, the in vivo relevance of PMT is undefined. Furthermore, it is unclear if PMT can recapitulate the biological activities of Nx in vivo. In this investigation, we tested the hypothesis that PMT recapitulates the biological activities of Nx and enhances GEM activity. This hypothesis was tested by comparing the efficacy of Nx and PMT using (i) athymic mice implanted with Capan-2 cells; (ii) a syngenic mouse model using C57BL/6 mice implanted with KPC-GFP-Luc cells; and (iii) a short term ex vivo model utilizing cells isolated from primary pancreatic tumors following surgical resection. Additionally, in vitro experiments were also done to assess the underlying molecular mechanism. Analysis of these data show that both Nx and PMT are well tolerated in vivo and a significant reduction in the levels of serum inflammatory cytokines including IL-6, granulocyte-colony stimulating factor (G-CSF), and CXCL1. Interestingly, animals receiving PMT, but not Nx, showed a trend towards decreased pancreatic tumor weight that was associated with histopathological changes. Investigation into the potential mechanism revealed that Nx and PMT mediated inhibition of STAT3, EP4, Src, TrkA, and RPS6 activities may contribute to the observed growth inhibitory and anti-inflammatory effects. Incredibly, our ex vivo analysis of patient derived PanCA cells demonstrated that both Nx and PMT could inhibit the growth of these cells. Collectively, our data demonstrates PMT recapitulates biological activities of Nx and that there is potential for developing PMT as an agent for clinical management of PanCA. Supported by NCCIH (R01 AT007448; APK) and VA-MERIT Award (I01 BX 000766; APK).
Citation Format: Amanda R. Muñoz, Roble Bedolla, Shih-Bo Huang, Xiaou Yang, Paul Rivas, Robert Reddick, Martha Hanes, Glenn Halff, Rita Ghosh, Addanki P. Kumar. Palmatine as a potential pancreatic cancer therapeutic agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5823.