| Popis: |
Anti-proliferative and cancer stem-cell targeting abilities of curcumin and resveratrol individually have been shown in different cancers. This project aimed to assess the activity of these compounds, alone and in combination in pancreatic cancer cell lines (PCCLs) and stellate cells. Anti-proliferation assays were performed for curcumin and resveratrol alone and in combination, combined with end point markers of activity including apoptosis and cell cycle arrest. Pancreatic cancer stem cell populations were defined using the cell surface markers CD44, CD24, ESA, CD133, ALDH-1 activity or sphere forming ability, and finally Nanog expression was assessed. The intracellular uptake of curcumin and its metabolites was analysed by HPLC. The PCCLs were more sensitive to curcumin than resveratrol, and combinations of these compounds showed anti-proliferative efficacy through apoptosis and cell cycle arrest at low, clinically achievable concentrations (CACs) in 2 out of 4 cell lines. Capan-1 cells exhibited the highest sensitivity to curcumin, which was able to enhance the effectiveness of resveratrol treatments in targeting cancer stem-like populations. Spheroid growth was significantly inhibited by curcumin and resveratrol combinations in Capan-1 cells, correlating with decreased ALDH1 activity and Nanog expression. In human pancreatic cancer tissue, various stem-like populations were identified based on expression of ALDH1 or CD24+/CD44+, which may provide a suitable target in vivo. Capan-1 cells metabolised curcumin to detectable amounts of curcumin glucuronide. However, curcumin metabolites did not show any significant activity at CACs. Curcumin alone may have activity against pancreatic cancer stem cells, and enhances efficacy at low concentrations when in combination with resveratrol. Capan-1 cells are able to internalise curcumin, and this cell line exhibited the greatest sensitivity to treatment. Overall, the results suggest that curcumin and resveratrol warrant further investigation as combination therapies for targeting cancer stem-like cells and stellate cells responsible for the dense stroma observed in pancreatic cancer. |
