Abstract 1895: Phytochemicals inhibit proliferation and promote death through NADPH oxidase and G6PD

Background & Aims: Pancreatic cancer is a very aggressive disease that is resistant to therapy. Evidence from population studies indicates a protective effect of fruits and vegetables in the diet on cancer including pancreatic cancer. In vitro and in vivo studies, including our own, suggest that several phytochemicals, such as ellagic acid and lycopene may be involved in this beneficial effect. In this study we investigated the effect of these phytochemicals, alone and in combination, on apoptosis and proliferation of pancreatic cancer cells in vitro, and we analyzed their mechanism of action. Methods: We measured the effect of ellagic acid and lycopene on DNA fragmentation using Cell Death Detection ELISA and on proliferation using ³H-thymidine incorporation into DNA in pancreatic cancer cell line MIA PaCa-2. Molecular signaling mechanisms were evaluated with Western. NF-kB activity was measured using electromobility shift assay. Metabolic phenotype of the cells was analyzed using mass spectrometry and the glucose molecule labeled with stable isotope D-glucose (1,2-¹³C₂). Results: Both lycopene and ellagic acid at doses from 0.1 to 30 μM induced increases in DNA fragmentation and inhibited proliferation in pancreatic cancer cells. Combinations of ellagic acid with lycopene at low doses (1 µM) induced a synergistic effect on DNA fragmentation and proliferation. Ellagic acid induced apoptosis by decreasing NF-kB activity in pancreatic cancer cells. Lycopene decreased NADPH oxidase activity. Combined compounds had a synergistic effect on the inhibition of glucose-6-phosphate dehydrogenase (G6PD) activity as measured by mass spectrometry leading to a synergistic inhibition of DNA synthesis. Conclusions: Combination of ellagic acid and lycopene induced a synergistic effect on apoptosis and proliferation in pancreatic cancer cells. The synergistic effect is due to different mechanisms of action of these phytochemicals leading to the inhibition of G6PD activity, a key step in DNA synthesis. Our study suggests a potentially beneficial role for combinations of ellagic acid and lycopene in prevention and treatment strategies of pancreatic cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1895.