Ellagic acid induces apoptosis through inhibition of nuclear factor kappa B in pancreatic cancer cells.
OBJECTIVE
To determine the effect of ellagic acid on apoptosis and proliferation in pancreatic cancer cells and to determine the mechanism of the pro-survival effects of ellagic acid.


METHODS
The effect of ellagic acid on apoptosis was assessed by measuring phosphatidylserine externalization, caspase activity, mitochondrial membrane potential and DNA fragmentation; and proliferation by measuring DNA thymidine incorporation. Mitochondrial membrane potential was measured in permeabilized cells, and in isolated mitochondria. Nuclear factor kappa B (NF-kappa B) activity was measured by electromobility shift assay (EMSA).


RESULTS
We show that ellagic acid, a polyphenolic compound in fruits and berries, at concentrations 10 to 50 mmol/L stimulates apoptosis in human pancreatic adenocarcinoma cells. Further, ellagic acid decreases proliferation by up to 20-fold at 50 mmol/L. Ellagic acid stimulates the mitochondrial pathway of apoptosis associated with mitochondrial depolarization, cytochrome C release, and the downstream caspase activation. Ellagic acid does not directly affect mitochondria. Ellagic acid dose-dependently decreased NF-kappa B binding activity. Furthermore, inhibition of NF-kappa B activity using IkB wild type plasmid prevented the effect of ellagic acid on apoptosis.


CONCLUSIONS
Our data indicate that ellagic acid stimulates apoptosis through inhibition of the prosurvival transcription factor NF-kappa B.
Edderkaoui
Mouad
M
Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, CA 90073, California, United States.
Odinokova
Irina
I
Ohno
Izumi
I
Gukovsky
Ilya
I
Go
Vay Liang W
VL
Pandol
Stephen J
SJ
Gukovskaya
Anna S
AS
D000230:Adenocarcinoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004610:Ellagic Acid / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*
D000972:Antineoplastic Agents, Phytogenic; D020672:I-kappa B Proteins; D016328:NF-kappa B; D004610:Ellagic Acid; D045304:Cytochromes c; D020169:Caspases