Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Cinnamaldehydes inhibit thioredoxin reductase and induce Nrf2: potential candidates for cancer therapy and chemoprevention

Chew, Eng-Hui, Nagle, Amrita A., Zhang, Yaochun, Scarmagnani, Silvia, Palaniappan, Puvithira, Bradshaw, Tracey D., Holmgren, Arne and Westwell, Andrew D. 2010. Cinnamaldehydes inhibit thioredoxin reductase and induce Nrf2: potential candidates for cancer therapy and chemoprevention. Free Radical Biology & Medicine 48 (1) , pp. 98-111. 10.1016/j.freeradbiomed.2009.10.028

Full text not available from this repository.


Trans-cinnamaldehyde (CA) and its analogs 2-hydroxycinnamaldehyde and 2-benzoyloxycinnamaldehyde have been reported to possess antitumor activity. CA is also a known Nrf2 activator. In this study, a series of ortho-substituted cinnamaldehyde analogs was synthesized and screened for antiproliferative and thioredoxin reductase (TrxR)-inhibitory activities. Whereas CA was weakly cytotoxic and TrxR inhibiting, hydroxy and benzoyloxy substitutions resulted in analogs with enhanced antiproliferative activity paralleling increased potency in TrxR inactivation. A novel analog, 5-fluoro-2-hydroxycinnamaldehyde, was identified as exhibiting the strongest antitumor effect (GI50 1.6 μM in HCT 116 cells) and TrxR inhibition (IC50 7 μM, 1 h incubation with recombinant TrxR). CA and its 2-hydroxy- and 2-benzoyloxy-substituted analogs possessed dual TrxR-inhibitory and Nrf2-inducing effects, both attributed to an active Michael acceptor pharmacophore. At lethal concentrations, TrxR-inhibitory potencies correlated with the compounds' antiproliferative activities. The penultimate C-terminal selenocysteine residue was shown to be a possible target. Conversely, at sublethal concentrations, these agents induced an adaptive antioxidant response through Nrf2-mediated upregulation of phase II enzymes, including TrxR induction. We conclude from the results obtained that TrxR inactivation contributes at least partly to cinnamaldehyde cytotoxicity. These Michael acceptor molecules can potentially be exploited for use in different concentrations in chemotherapeutic and chemopreventive strategies.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RS Pharmacy and materia medica
Publisher: Elsevier
ISSN: 0891-5849
Last Modified: 04 Jun 2017 01:57

Citation Data

Cited 127 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item