Flavonoid apigenin modified gene expression associated with inflammation and cancer and induced apoptosis in human pancreatic cancer cells through inhibition of GSK-3β/NF-κB signaling cascade.
METHODS
The objective was to examine the inhibitory effects of citrus fruit bioactive compounds on BxPC-3 and PANC-1 human pancreatic cancer cells, focusing on the antiproliferative mechanism of action of the flavonoid apigenin related to the glycogen synthase kinase-3β/nuclear factor kappa B signaling pathway.


RESULTS
Flavonoids, limonoids, phenolic acids, and ascorbic acid were tested for cytotoxic effects on BxPC-3 and PANC-1 cells; apigenin was the most potent (IC50 = 23 and 12 μM for 24 and 48 h for BxPC-3 and IC50 = 71 and 41 μM for 24 and 48 h for PANC-1). Apigenin induced pancreatic cell death through inhibition of the glycogen synthase kinase-3β/nuclear factor kappa B signaling pathway. Apigenin arrested cell cycle at G2 /M phase (36 and 32% at 50 μM for BxPC-3 and PANC-1, respectively) with concomitant decrease in the expression of cyclin B1. Apigenin activated the mitochondrial pathway of apoptosis (44 and 14% at 50 μM for BxPC-3 and PANC-1, respectively) and modified the expression of apoptotic proteins. Apigenin highly upregulated the expression of cytokine genes IL17F (114.2-fold), LTA (33.1-fold), IL17C (23.2-fold), IL17A (11.3-fold), and IFNB1 (8.9-fold) in BxPC-3 cells, which potentially contributed to the anticancer properties.


CONCLUSIONS
Flavonoids have a protective role in pancreatic cancer tumorigenesis.
Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, IL, USA.
Jodee L
JL
Johnson
Elvira Gonzalez
EG
de Mejia
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D047310:Apigenin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000494:pharmacology; D020134:Catalytic Domain; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002957:Citrus / Q000737:chemistry; D016207:Cytokines / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007249:Inflammation / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D005419:Flavonoids; D016328:NF-kappa B; D047310:Apigenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D001205:Ascorbic Acid
Apigenin; Flavonoids; GSK-3β; NF-κB; Pancreatic cancer