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.
Highlights
Due to aberrant metabolic events and abnormal proliferative growth phenotypes, reactive oxygen species (ROS) levels are commonly elevated in cancer cells [references cited in 1, 2]
A series of analogs containing a Michael acceptor-based 3-(2-oxopropylidene) indolin-2-one scaffold was evaluated for cytotoxicity towards human-derived colorectal HCT 116 and breast MCF-7 carcinoma cells over a duration of 72 h
We found a majority of the compounds displayed a good correlation between antiproliferative activities toward two human cancer cell lines and thioredoxin reductase (TrxR) inhibition, which has several important implications
Summary
Due to aberrant metabolic events and abnormal proliferative growth phenotypes, reactive oxygen species (ROS) levels are commonly elevated in cancer cells [references cited in 1, 2]. The selective targeting of cancer cells on the basis of different redox states between normal and tumor cells is a feasible strategy [1, 3,4,5,6], when it involves targeting a redox adaptive mechanism that confers drug resistance [2]. In this context, inhibition of www.impactjournals.com/oncotarget the thioredoxin (Trx) system has emerged as a promising redox-modulating strategy for anticancer therapy. Through Trx’s involvement in DNA synthesis, its role in the enzymatic regulation of several redox-sensitive transcription factors, and its direct binding to and inhibition of apoptosis signal regulating kinase 1 (ASK1), the Trx system is highly important for multiple cellular aspects involving cell survival and proliferation [12, 13]
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