Food-derived polyphenols inhibit pancreatic cancer growth through mitochondrial cytochrome C release and apoptosis.
There is increasing evidence that food-derived polyphenols have a beneficial effect for cancers. Our purpose was to determine the effect and mechanism of action of these compounds on pancreatic cancer. We measured effects of quercetin on pancreatic cancer in a nude mouse model. We also investigated the effects of quercetin, rutin, trans-resveratrol and genistein on apoptosis and underlying signaling in pancreatic carcinoma cells in vitro. Quercetin decreased primary tumor growth, increased apoptosis and prevented metastasis in a model of pancreatic cancer. In vitro quercetin and trans-resveratrol, but not rutin, markedly enhanced apoptosis, causing mitochondrial depolarization and cytochrome c release followed by caspase-3 activation. In addition, the effect of a combination of quercetin and trans-resveratrol on mitochondrial cytochrome c release and caspase-3 activity was greater than the expected additive response. The inhibition of mitochondrial permeability transition prevented cytochrome c release, caspase-3 activation and apoptosis caused by polyphenols. Nuclear factor-kappa B activity was inhibited by quercetin and trans-resveratrol, but not genistein, indicating that this transcription factor is not the only mediator of the polyphenols' effects on apoptosis. The results suggest that food-derived polyphenols inhibit pancreatic cancer growth and prevent metastasis by inducing mitochondrial dysfunction, resulting in cytochrome c release, caspase activation and apoptosis.
Mouria
Michelle
M
Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, CA 90073, USA.
Gukovskaya
Anna S
AS
Jung
Yoon
Y
Buechler
Peter
P
Hines
Oscar J
OJ
Reber
Howard A
HA
Pandol
Stephen J
SJ
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000627:therapeutic use*; D005502:Food; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000201:enzymology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010636:Phenols / Q000627:therapeutic use*; D011108:Polymers / Q000627:therapeutic use*; D014162:Transfection; D014407:Tumor Cells, Cultured
D017304:Annexin A5; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D005419:Flavonoids; D016328:NF-kappa B; D010636:Phenols; D011108:Polymers; D016572:Cyclosporine; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases