55. Myricetin a Novel Natural Antineoplastic Agent Decreases Progression of Human Pancreatic Cancer Via Inhibition of Akt Kinase and Erk Pathways

Pawel Zwolak; Daniel Borja-Cacho; Phoebe Phillips; Vikas Dudeja; Rajinder K. Dawra; Rupjyoti Talukdar; Rohit K. Chugh; Arkadiusz Z. Dudek; Selwyn M. Vickers; Ashok K. Saluja

doi:10.1016/j.jss.2007.12.063

Myricetin is a major polyphenolic flavonoid found in fruits, vegetables and red wine and has been shown to demonstrate anti-cancer activities. In the present study, we have evaluated the effect of myricetin in pancreatic cancer and have elucidated the mechanism by which myricetin kills pancreatic cancer cell. Methods: Pancreatic cancer cells (MiaPaCa-2/PANC-1, S2013, and S2VP10) and normal pancreatic ductal cells were treated with myricetin 25-200 μM. Cell viability was evaluated by proliferation assay. The parameters of apoptosis, Annexin V and Caspase 3/9 activation were measured by flow cytometry and luminescence-based caspase assay, respectively. The effect of myricetin on the activation of Akt, MAPK, and p38 was measured by evaluating the level of the active phosphorylated form of these enzymes by western blotting. Orthotopic Pancreatic Tumors in Nude Mice: MiaPaca-2 cells, were resuspended in matrigel at a concentration of 1 million cells per 10μl and injected to female nude mice. Surgery protocol; a small left abdominal vertical flank incision was made, and the spleen and pancreas were exposed. MiaPaCa-2 tumor cells were injected into the tail of the pancreas with a Hamilton syringe. Both layers of the abdominal wound were closed with stitches. Seven days after injection of MiaPaca-2 cells, animals were randomized into two treatment groups: control (vehicle-DMSO) and myricetin 30 mg/kg given as daily intraperitoneal injections. Tumor volume was evaluated using Ultrasound HP Sonos 5500 machine equipped with a 15-6L linear array transducer with a transmit frequency of 63 MHz. for cross-sectional images. Results: Myricetin reduced the viability of pancreatic cancer cell lines in a dose-dependent and time-dependent fashion without affecting the viability of normal pancreatic ductal cells. Myricetin induces apoptosis in pancreatic cancer cells, as suggested by increased annexin V staining and activation of caspase 3/9. Myricetin reduced the levels of phosphorilated p-Akt, p-MAPK, and p-P38 as measured by western blot, which suggests their inactivation. In animal orthotopic model after daily i.p injections of myricetin at the dose of 30 mg/kg, the tumor volume was significantly reduced on day 21 in myricetin group 19.61 1.38 mm3 vs. control group 46.67 6.52 mm3,P<0.0081. Moreover, myricetin treated mice did not show any signs of drug toxicity. Conclusion: in Vitro, myricetin induces apoptotic cell death in pancreatic cancer cells without influencing the viability of normal ductal cells. In vivo, mice treated with myricetin had significantly reduced tumor volume without any side effect related to compound. Based on our preliminary results, we postulate that myricetin may be a very potent antineoplastic agent for treatment of this devastating disease.

55. Myricetin a Novel Natural Antineoplastic Agent Decreases Progression of Human Pancreatic Cancer Via Inhibition of Akt Kinase and Erk Pathways

View Online

Abstract

Details

Metrics