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

Chew, Eng‐Hui; Nagle, Amrita A.; Yao-chun, Zhang; Scarmagnani, Silvia; Palaniappan, P. L. R. M.; Bradshaw, Tracey D.; Holmgren, Arne; Westwell, Andrew D.

doi:10.1016/j.freeradbiomed.2009.10.028

Cited by 136 publications

(83 citation statements)

References 47 publications

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“…1), which is reminiscent of many known TrxR inhibitors, such as curcumin and its analogues (20,51,52), cinnamaldehydes (53,54), adenanthin (14), gambogic acid (18), and xanthohumol analogues (13). Thus we speculated that PTL might be also an inhibitor of TrxR.…”

Section: Resultsmentioning

confidence: 99%

Targeting Thioredoxin Reductase by Parthenolide Contributes to Inducing Apoptosis of HeLa Cells

Duan

Zhang

Yao

et al. 2016

Journal of Biological Chemistry

111

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Section: Resultsmentioning

confidence: 99%

Targeting Thioredoxin Reductase by Parthenolide Contributes to Inducing Apoptosis of HeLa Cells

Duan

Zhang

Yao

et al. 2016

Journal of Biological Chemistry

111

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“…We previously reported that hydroxy and fluorine substitutions render strong TrxR inhibitory character to cinnamaldehydes and compounds containing a 1,5-diphenyl-pent-1-en-3-one (DDPen) or 1,3-diphenyl-prop-1-en-3-one (DPPro; also known as chalcone) pharmacophore [47, 48]. In the present study, the evaluated indolin-2-one compounds contain the 3-(2-oxopropylidene)indolin-2-one backbone, which possesses two conjugated α,β-unsaturated carbonyl groups as Michael acceptors.…”

Section: Discussionmentioning

confidence: 99%

Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads

et al. 2016

Self Cite

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Several compounds bearing the indolinone chemical scaffold are known to possess anticancer properties. For example, the tyrosine kinase inhibitor sunitinib is an arylideneindolin-2-one compound. The chemical versatility associated with structural modifications of indolinone compounds underlies the potential to discover additional derivatives possessing anticancer properties. Previously synthesized 3-(2-oxoethylidene)indolin-2-one compounds, also known as supercinnamaldehyde (SCA) compounds in reference to the parent compound 1 [1-methyl-3(2-oxopropylidene)indolin-2-one], bear a nitrogen-linked α,β-unsaturated carbonyl (Michael acceptor) moiety. Here we found that analogs bearing N-substituents, in particular compound 4 and 5 carrying an N-butyl and N-benzyl substituent, respectively, were strongly cytotoxic towards human HCT 116 colorectal and MCF-7 breast carcinoma cells. These compounds also displayed strong thioredoxin reductase (TrxR) inhibitory activity that was likely attributed to the electrophilicity of the Michael acceptor moiety. Their selectivity towards cellular TrxR inhibition over related antioxidant enzymes glutathione reductase (GR), thioredoxin (Trx) and glutathione peroxidase (GPx) was mediated through targeting of the selenocysteine (Sec) residue in the highly accessible C-terminal active site of TrxR. TrxR inhibition mediated by indolin-2-one compounds led to cellular Trx oxidation, increased oxidative stress and activation of apoptosis signal-regulating kinase 1 (ASK1). These events also led to activation of p38 and JNK mitogen-activated protein kinase (MAPK) signaling pathways, and cell death with apoptotic features of PARP cleavage and caspase 3 activation. In conclusion, these results suggest that indolin-2-one-based compounds specifically targeting TrxR may serve as novel drug leads for anticancer therapy.

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“…The presence of the substituents at the ortho, but not para or meta, positions of the aromatic ring(s) significantly increase the cytotoxicity, highlighting a so-called ortho effect (Dai et al, 2015). Previously, the presence of ortho effect was also proved to significantly strengthen the cytotoxicity of cinnamaldehydes (Chew et al, 2010), chalcones (Gan et al, 2013) and mono-carbonyl curcumin analogs (Dai et al, 2015). (3) 1a showed less active than curcumin after treatment for 24 h against NCI-H460 cells, which was apposed to the results of 48 h. The phenomenon may be due to the cellular uptake of 1a and curcumin in NCI-H460 cells.…”

Section: Cytotoxicity and Sarmentioning

confidence: 99%

2,2′-Fluorine mono-carbonyl curcumin induce reactive oxygen species-Mediated apoptosis in Human lung cancer NCI-H460 cells

Liu

Zeng

Chen

et al. 2016

European Journal of Pharmacology

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

Cited by 136 publications

References 47 publications

Targeting Thioredoxin Reductase by Parthenolide Contributes to Inducing Apoptosis of HeLa Cells

Targeting Thioredoxin Reductase by Parthenolide Contributes to Inducing Apoptosis of HeLa Cells

Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads

2,2′-Fluorine mono-carbonyl curcumin induce reactive oxygen species-Mediated apoptosis in Human lung cancer NCI-H460 cells

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