Ellagic Acid and Embelin Affect Key Cellular Components of Pancreatic Adenocarcinoma, Cancer, and Stellate Cells

Abstract

Ellagic acid is a polyphenolic phytochemical present in many fruits and nuts with anticancer properties demonstrated in experimental tumor studies. Embelin is a benzoquinone phytochemical isolated from the Japanese herb Ardisiae Japonicae and has been shown to induce apoptosis in cancer cells. We found that ellagic acid and embelin each dose-dependently increased apoptosis and inhibited proliferation in human pancreatic cancer cells, MIA PaCa-2 and HPAF-II cells, and in pancreatic stellate cells, which are progenitors of pancreatic cancer desmoplasia. In each of these cell types, combinations of ellagic acid and embelin at low micromolar concentrations (0.5–3 μM) induced synergistic increases in apoptosis and decreases in proliferation. Ellagic acid decreased NF-κB transcriptional activity, whereas embelin decreased STAT-3 phosphorylation and protein expression of its downstream target survivin in cancer cells. In vivo dietary ellagic acid alone or in combination with embelin decreased tumor size and tumor cellularity in a subcutaneous xenograft mouse model of pancreatic cancer. These results show that ellagic acid and embelin interact with divergent intracellular signaling pathways resulting in augmentation of apoptosis and inhibition of proliferation at low micromolar concentrations for the key cellular components of pancreatic adenocarcinoma.

ACKNOWLEDGMENTS

We acknowledge the support of the Animal and Morphology Cores of the UCLA Center for Excellence in Pancreatic Diseases (P01AT003960) for their assistance with the xenograft model of pancreatic cancer. This work was supported by the UCLA Center for Excellence in Pancreatic Diseases (NCCAM: 1 P01 AT003960), the Department of Veterans Affairs, and two NIAAA awards (K01 AA019996 to Mouad Edderkaoui and R01 AA019954 to Aurelia Lugea). Mouad Edderkaoui and Aurelia Lugea contributed equally to this work.