title: Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads.
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.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, S117543, Republic of Singapore.
authors.forename: Kamila K
authors.initials: KK
authors.lastname: Kaminska
authors.affiliation: UCL School of Pharmacy, University College London, London WC1N 1AX, United Kingdom.|Current address: École Normale Supérieure, PSL Research University, Département de Chimie, Sorbonne Universités, UPMC Univ Paris 06, CNRS UMR 7203 LBM, 75005 Paris, France.
authors.forename: Helene C
authors.initials: HC
authors.lastname: Bertrand
authors.affiliation: UCL School of Pharmacy, University College London, London WC1N 1AX, United Kingdom.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tajima
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
authors.forename: William C
authors.initials: WC
authors.lastname: Stafford
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
authors.forename: Qing
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, S117543, Republic of Singapore.
authors.forename: Wan
authors.initials: W
authors.lastname: Chen
authors.affiliation: UCL School of Pharmacy, University College London, London WC1N 1AX, United Kingdom.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Wells
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
authors.forename: Elias S J
authors.initials: ES
authors.lastname: Arner
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, S117543, Republic of Singapore.
authors.forename: Eng-Hui
authors.initials: EH
authors.lastname: Chew
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D000975:Antioxidants / Q000378:metabolism; D020134:Catalytic Domain; D002417:Cattle; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D051379:Mice; D009285:Naphthoquinones / Q000737:chemistry; D018384:Oxidative Stress; D000072417:Protein Domains; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D017279:Selenocysteine / Q000737:chemistry; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D007211:Indoles; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C491203:TXN protein, human; C456900:indolin-2-one; D017279:Selenocysteine; D013879:Thioredoxins; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; C005134:juglone
keywords: anticancer; indolin-2-one; selenocysteine; supercinnamaldehyde; thioredoxin reductase