Curcumin analog 1, 5-bis (2-trifluoromethylphenyl)-1, 4-pentadien-3-one exhibits enhanced ability on Nrf2 activation and protection against acrolein-induced ARPE-19 cell toxicity.

Abstract

Curcumin, a phytochemical agent in the spice turmeric, has received increasing attention for its anticancer, anti-inflammatory and antioxidant properties. However, application of curcumin has been limited due to its insolubility in water and poor bioavailability both clinically and experimentally. In addition, the protective effects and mechanisms of curcumin in eye diseases have been poorly studied. In the present study, we synthesized a curcumin analog, 1, 5-bis (2-trifluoromethylphenyl)-1, 4-pentadien-3-one (C3), which displayed improved protective effect against acrolein-induced toxicity in a human retinal pigment epithelial cell line (ARPE-19). At 5 μM, curcumin completely protected against acrolein-induced cell oxidative damage and preserved GSH levels and mitochondrial function. Surprisingly, C3 displayed a complete protective effect at 0.5 μM, which was much more efficient than curcumin. Both 0.5 μM C3 and 5 μM curcumin induced Nrf2 nuclear translocation and Nrf2 target genes transcription similarly. Experiments using Nrf2 siRNA showed that the protective effects of curcumin and C3 were eliminated by Nrf2 knockdown. Additionally, both curcumin and C3 activated the PI3/Akt pathway, however, Nrf2 activation was independent of this pathway, and therefore, we hypothesized that both curcumin and C3 activated phase II enzymes via directly disrupting the Nrf2/Keap1 complex and promoting Nrf2's nuclear translocation. Since acrolein challenge of ARPE-19 cells has been used as a model of smoking and age-related macular degeneration (AMD), we concluded that the curcumin analog, C3, may be a more promising drug candidate for its potential application for the prevention and treatment of eye diseases, such as AMD.

• Authors: Yuan Li, Xuan Zou, Ke Cao, Jie Xu, Tingting Yue, Fang Dai, Bo Zhou, Wuyuan Lu, Zhihui Feng, Jiankang Liu
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 272 Issue 3 Pg. 726-35 (Nov 01 2013) ISSN: 1096-0333 [Electronic] United States
• PMID: 23954767 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013.

Chemical References

• Antioxidants
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Acrolein
• Curcumin

Topics

• Acrolein (antagonists & inhibitors, toxicity)
• Antioxidants (pharmacology)
• Cell Line
• Cell Survival (drug effects, physiology)
• Curcumin (analogs & derivatives, pharmacology)
• Cytoprotection (drug effects, physiology)
• Dose-Response Relationship, Drug
• Humans
• NF-E2-Related Factor 2 (metabolism)
• Oxidative Stress (drug effects, physiology)
• Retinal Pigment Epithelium (drug effects, metabolism)