Cinnamaldehydes inhibit thioredoxin reductase and induce Nrf2: potential candidates for cancer therapy and chemoprevention.
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 (GI(50) 1.6 microM in HCT 116 cells) and TrxR inhibition (IC(50) 7 microM, 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.
Chew
Eng-Hui
EH
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543. phaceh@nus.edu.sg
Nagle
Amrita A
AA
Zhang
Yaochun
Y
Scarmagnani
Silvia
S
Palaniappan
Puvithira
P
Bradshaw
Tracey D
TD
Holmgren
Arne
A
Westwell
Andrew D
AD
D000171:Acrolein / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D013237:Stereoisomerism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000171:Acrolein; D013880:Thioredoxin-Disulfide Reductase; C012843:cinnamaldehyde