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

Kaminska, KK; Bertrand, HC; Tajima, H; Stafford, WC; Cheng, Q; Chen, W; Wells, G; ... Chew, EH; + view all (2016) Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads. Oncotarget , 7 (26) pp. 40233-40251. 10.18632/oncotarget.9579. Green open access

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Abstract

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.

Type: Article
Title: Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads
Open access status: An open access version is available from UCL Discovery
DOI: 10.18632/oncotarget.9579
Publisher version: http://dx.doi.org/10.18632/oncotarget.9579
Language: English
Additional information: Copyright © 2016 Impact Journals, LLC. Licensed under the Creative Commons Attribution License (CC BY 3.0) (https://creativecommons.org/licenses/by/3.0/); authors retain ownership of the copyright for their article, but authors allow anyone to download, reuse, reprint, modify, distribute, and/or copy articles in Oncotarget journal, so long as the original authors and source are cited.
Keywords: anticancer, indolin-2-one, selenocysteine, supercinnamaldehyde, thioredoxin reductase
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > SoP Pharmaceutical and Bio Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1497166
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