Ellagic acid inhibits human pancreatic cancer growth in Balb c nude mice

• Dysregulation of the PI3K/Akt, Notch and Shh pathways can occur in pancreatic cancer, providing several potential drug targets.
• Ellagic acid inhibits the PI3K/Akt, Notch and Shh pathways in pancreatic cancer.
• The inhibition of multiple pathways by a natural product can overcome limitations of one pathway inhibition.
• Clinical studies are underway evaluating agents that inhibit the PI3K/Akt, Notch and Shh pathways.

Ellagic acid (EA) is a polyphenol found in several plants and fruits. The objectives of this study were to examine the molecular mechanisms by which EA inhibits pancreatic cancer growth in Balb C nude mice. PANC-1 cells were injected subcutaneously into Balb c nude mice, and tumor-bearing mice were treated with EA. The expression of Akt, Shh and Notch and their target gene products were measured by the immunohistochemistry and Western blot analysis. Treatment of PANC-1 xenografted mice with EA resulted in significant inhibition in tumor growth which was associated with suppression of cell proliferation and caspase-3 activation, and induction of PARP cleavage. EA inhibited the expression of Bcl-2, cyclin D1, CDK2, and CDK6, and induced the expression of Bax in tumor tissues compared to untreated control group. EA inhibited the markers of angiogenesis (COX-2, HIF1α, VEGF, VEGFR, IL-6 and IL-8), and metastasis (MMP-2 and MMP-9) in tumor tissues. Furthermore, treatment of mice with EA caused a significant inhibition in phospho-Akt, Gli1, Gli2, Notch1, Notch3, and Hey1. EA also reversed epithelial to mesenchymal transition by up-regulating E-cadherin and inhibiting the expression of Snail, MMP-2 and MMP-9. These data suggest that EA can inhibit pancreatic cancer growth, angiogenesis and metastasis by suppressing Akt, Shh and Notch pathways. In view of the fact that EA could effectively inhibit human pancreatic cancer growth by suppressing Akt, Shh and Notch pathways, our findings suggest that the use of EA would be beneficial for the management of pancreatic cancer.