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

Mol Nutr Food Res. 2013 Dec;57(12):2112-27. doi: 10.1002/mnfr.201300307. Epub 2013 Aug 14.


Scope: 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.

Methods and 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.

Conclusion: Flavonoids have a protective role in pancreatic cancer tumorigenesis.

Keywords: Apigenin; Flavonoids; GSK-3β; NF-κB; Pancreatic cancer.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology
  • Apigenin / pharmacology*
  • Apoptosis / drug effects
  • Ascorbic Acid / pharmacology
  • Catalytic Domain
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Citrus / chemistry
  • Cytokines / genetics
  • Drug Screening Assays, Antitumor
  • Flavonoids / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Inflammation / genetics
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Signal Transduction / drug effects


  • Antineoplastic Agents, Phytogenic
  • Cytokines
  • Flavonoids
  • NF-kappa B
  • Apigenin
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • Ascorbic Acid