A curcumin derivative that inhibits vinyl carbamate-induced lung carcinogenesis via activation of the Nrf2 protective response.
Antioxid Redox Signal. 2015 Apr 19. Epub 2015 Apr 19. PMID: 25891177
AIMS: Lung cancer has a high worldwide morbidity and mortality. The employment of chemopreventive agents is effective to reduce lung cancer. Nrf2 mitigates insults from both exogenous and endogenous sources, and thus has been verified as a target for chemoprevention. Curcumin has long been recognized as a chemopreventive agent, but poor bioavailability and weak Nrf2 induction have prohibited clinical application. Thus, we have developed new curcumin derivatives and tested their Nrf2 induction.
RESULTS: Based on curcumin, we synthesized curcumin analogues with five carbon linkages and established a structure-activity relationship for Nrf2 induction. Among these derivatives, bis[2-hydroxybenzylidene]acetone (BHBA) was one of the most potent Nrf2 inducers with minimal toxicity and improved pharmacological properties and was thus selected for further investigation. BHBA activated the Nrf2 pathway in the canonical Keap1-Cys151-dependent manner. Furthermore, BHBA was able to protect human lung epithelial cells against sodium arsenite [As(III)]-induced cytotoxicity. More importantly, in an in vivo vinyl carbamate-induced lung cancer model in A/J mice, pre-administration of BHBA significantly reduced lung adenocarcinoma, while curcumin failed to show any effects even at high doses.
INNOVATION: The curcumin derivative BHBA is a potent inducer of Nrf2. It was demonstrated to protect against As(III) toxicity in lung epithelial cells in an Nrf2 dependent manner. Furthermore, compared to curcumin BHBA displayed improved chemopreventive activities in a carcinogen-induced lung cancer model.
CONCLUSION: Taken together, our results demonstrate that BHBA, a curcumin analogue with improved Nrf2-activating and chemopreventive activities both in vitro and in vivo, could be developed into a chemoprotective pharmacological agent.