Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads
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Kamila K. Kaminska1, Helene C. Bertrand2,4, Hisashi Tajima2, William C. Stafford3, Qing Cheng3, Wan Chen1, Geoffrey Wells2, Elias S.J. Arner3, Eng-Hui Chew1
1Department of Pharmacy, Faculty of Science, National University of Singapore, S117543, Republic of Singapore
2UCL School of Pharmacy, University College London, London WC1N 1AX, United Kingdom
3Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden
4Current address: École Normale Supérieure, PSL Research University, Département de Chimie, Sorbonne Universités, UPMC Univ Paris 06, CNRS UMR 7203 LBM, 75005 Paris, France
Eng-Hui Chew, email: email@example.com
Keywords: anticancer, indolin-2-one, supercinnamaldehyde, selenocysteine, thioredoxin reductase
Received: October 28, 2015 Accepted: April 18, 2016 Published: May 24, 2016
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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