Cyclometalated Gold(III) Complexes Containing N‐Heterocyclic Carbene Ligands Engage Multiple Anti‐Cancer Molecular Targets

Fung, Sin Ki; Zou, Taotao; Cao, Bei; Lee, Pui‐Yan; Fung, YS; Hu, Di; Lok, Chun‐Nam; Che, Chi‐Ming

doi:10.1002/ange.201612583

Cited by 35 publications

(13 citation statements)

References 69 publications

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“…It has already been shown that substances acting through the mitochondrial, internal pathway of apoptosis changed the activity or concentration of proapoptotic and antiapoptotic proteins [18,19]. In addition, it has already been shown that gold complexes could induce apoptosis by activating the mitochondrial pathway of apoptosis [26,29]. Activation of caspase-8 is typical for the external (receptor) pathway of apoptosis, while increased active Bax and/or decreased Bcl-2 is rather connected with the internal (mitochondrial) pathway.…”

Section: Discussionmentioning

confidence: 99%

New gold pincer-type complexes induce caspase-dependent apoptosis in human cancer cells in vitro

et al. 2021

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Background / Aim. We investigated cytotoxicity of Au(III) complexes with pincer type ligands against cervical carcinoma cells (HeLa), breast cancer cells (MDA-MB-231 and 4T1) and colon carcinoma cells (HCT116 and CT26). We also examined the type and mechanism of cell death that these complexes induced in cancer cells. Methods.Cytotoxicity of Au(III) complexes was investigated by MTT assay. Apoptosis of treated cancer cells was measured by flow cytometry and applying Annexin V/7AAD staining. The expressions of active proapoptotic protein Bax, antiapoptotic protein Bcl-2 and the percentage of cells containing cleaved caspase-3 in treated cancer cells was determined by flow cytometry. Results. Complex 1 showed the most potent anti-tumor effect on HeLa cells, both compared to other two examined gold complexes and compared to cisplatin. The IC50 values on HeLa cells after 72 hours were 1.3 ± 0.4 μM, 3.4 ± 1.3 μM, 5.7 ± 0.6 μM, 26.7 ± 6.5 μM for complexes 1, 2, 3 and cisplatin, respectively. Complex 1 also exhibited highest cytotoxicity against MDA-MB-231 and HCT116 cells compared to other tested compounds. The results of Annexin V/7AAD staining showed that all three complexes induced apoptosis in treated cells. Our gold(III) complexes induced apoptosis by caspasedependent mechanism, but we did not observe that an activation of the internal pathway of apoptosis occurred in treated cancer cells. Conclusion. According to the results of our in vitro study, all three compounds and especially complex 1 are promising candidates for a new generation of anticancer drugs. Uvod. Ispitivali smo citotoksičnost Au(III) kompleksa sa ligandima tipa pincer protiv ćelija karcinoma grlića materice (HeLa), ćelija raka dojke (MDA-MB-231 i 4T1) i ćelija karcinoma kolona (HCT116 i CT26). TakoĎe smo ispitali tip i mehanizam ćelijske smrti koji su ovi kompleksi indukovani u ćelijama raka. Metode. Citotoksičnost Au(III) kompleksa je ispitivana pomoću MTT testa. Apoptoza tretiranih ćelija raka je merena protočnom citometrijom i primenom bojenja Aneksin V/7AAD. Ekspresija aktivnog proapoptotičnog proteina Bax, antiapoptotskog proteina Bcl-2 i procenat ćelija koje sadrže aktivnu kaspazu-3 u tretiranim ćelijama raka je odreĎena protočnom citometrijom. Rezultati. Kompleks 1 je pokazao najsnažniji antitumorski efekat na HeLa ćelije, kako u 4 poreĎenju sa drugim ispitivanim kompleksima zlata, tako i u poreĎenju sa cisplatinom.Vrednosti IC50 kompleksa zlata na HeLa ćelije nakon 72 sata bile su 1,3 ± 0,4 μM, 3,4 ± 1,3 μM, 5,7 ± 0,6 μM, 26,7 ± 6,5 μM za komplekse 1, 2, 3 i cisplatin. Kompleks 1 je takoĎe pokazao najvišu citotoksičnost prema MDA-MB-231 i HCT116 ćelijama u poreĎenju sa drugim testiranim jedinjenjima. Rezultati bojenja aneksinomV/7AAD pokazali su da sva tri kompleksa indukuju apoptozu u tretiranim ćelijama. Naši kompleksi zlata(III) indukovali su apoptozu mehanizmom koji je zavisio od kaspaze, ali nismo pokazali da je u tretiranim ćelijama raka došlo do aktivacije unutrašnjeg puta apoptoze. Zakljuĉak. Prema rezultatima naše in vitro studij...

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Section: Discussionmentioning

confidence: 99%

New gold pincer-type complexes induce caspase-dependent apoptosis in human cancer cells in vitro

et al. 2021

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“…Proteomic analysiso fH ela cells highlighted the modulation of the eukaryotic initiation factor 2( eIF2) signalling pathway involved in the synthesis of proteins upon treatment with 32.P roteomic data are in good agreement with the identified targets since VIM, NPM and YB-1, three of the identified protein targets, are involved in eIF2 signalling pathway modulation. [76] Interestingly,p roteins involved in protein synthesis have been similarly found to be down-regulated upon treatment with the (C^N^N)Au III complex 25 (Figure 8), pointingt oward ag eneral mode of action for cyclometalated Au III complexes. [67] Replacing the central pyridine ring by ap yrazinee nhanced the photoemissive properties of thec orresponding (C^N^C)Au III complexes andi ncreases the tendency toward pstacking and H-bonding.…”

Section: Gold(iii) Complexes With Cyclometalated Ligands (C^n)au III mentioning

confidence: 92%

“…Then the alkynyl group was used to graft an azido-biotin fragment by the usual click-reaction, which enables the detection of 32/protein conjugatesw ith streptavidin-peroxidase. [76] Only six proteins were observed to be boundt o32;t hese were identified as heat shock protein 60 (HSP60), vimentin (VIM), nucleoside diphosphatek inase A( NDKA), nucleophosmin (NPM), nuclease-sensitive element binding protein (Y box binding protein, YB-1), and peroxiredoxin 1( PRDX1) which are all reported possible anticancer targets.W hen the same experiment was carried out with Hela, NCI-H460 and HCT116 the same six proteins were identified. Proteomic analysiso fH ela cells highlighted the modulation of the eukaryotic initiation factor 2( eIF2) signalling pathway involved in the synthesis of proteins upon treatment with 32.P roteomic data are in good agreement with the identified targets since VIM, NPM and YB-1, three of the identified protein targets, are involved in eIF2 signalling pathway modulation.…”

Section: Gold(iii) Complexes With Cyclometalated Ligands (C^n)au III mentioning

confidence: 99%

Gold(III) Complexes for Antitumor Applications: An Overview

Bertrand

Williams

Bochmann

2018

Chemistry A European J

114

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Gold(III) complexes have emerged as a versatile and effective class of metal-based anticancer agents. The development of various types of ligands capable of stabilizing the Au cation and preventing its reduction under physiological conditions, such as chelating nitrogen-donors, dithiocarbamates and C^N cyclometalled ligands, has opened the way for the exploration of their potential intracellular targets and action mechanisms. At the same time, the bioconjugation of Au complexes has emerged as a promising strategy for improving the selectivity of this class of compounds for cancer cells over healthy tissues, and recent developments have shown that combining gold complexes with molecular structures that are specifically recognized by the cell can exploit the cell's own transport mechanisms to improve selective metal uptake.

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“…18 Multiple targets were reported for a cyclometallated gold(III) complex by photo-crosslinking and subsequent 2D-PAGE and MS analysis of the fluorescent spots. 19,20 A similar strategy showed the mitochondrial heat shock protein 60 as a target for gold(III) porphyrins. 21 Furthermore, putative targets for RAPTA compounds were suggested by a target profiling approach.…”

Section: Introductionmentioning

confidence: 99%

Time-dependent shotgun proteomics revealed distinct effects of an organoruthenium prodrug and its activation product on colon carcinoma cells

et al. 2019

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Time-dependent shotgun proteomics revealed distinct effects of an organoruthenium prodrug and its activation product on colon carcinoma cellsThe unravelling of target interactions in cancer cells is a crucial process for identifying promising metal-based anticancer agents. Therefore, target profiles were analysed in a time-dependent manner using proteomics techniques by accounting for the hydrolysis kinetics of plecstatin, an organometallic ruthenium(arene) derivative. While the intact prodrug provoked a cytoprotective integrated stress response, which was further verified by gene expression studies, the activated species was responsible for the target engagement with plectin, the previously validated protein target. As featured in:ISSN 1756-591X Activation kinetics of metallo-prodrugs control the types of possible interactions with biomolecules. The intact metallo-prodrug is able to engage with potential targets by purely non-covalent bonding, while the activated metallodrug can form additional coordination bonds. It is hypothesized that the additional coordinative bonding might be favourable with respect to the target selectivity of activated metallodrugs. Thus, a time-dependent shotgun proteomics study was conducted in HCT116 colon carcinoma cells with plecstatins, which are organoruthenium anticancer drug candidates. First, the target selectivity was evaluated in a time-dependent fashion, which accounted for their hydrolysis kinetics. The binding selectivity increased from 50-to 160-fold and the average specificity from 0.72 to 0.86, respectively, from the 2 h to the 4 h target profiling experiment. Target profiling after 19 h did not reveal significant enrichments, possibly due to deactivation of the probe via arene cleavage. Up to 450 interactors were identified in the target profiling experiments. A plecstatin analogue that substituted a hydrogen bond acceptor with a hydrogen bond donor abrogated the target selectivity for plectin in HCT116 whole cell lysates, underlining the necessity of this hydrogen bond acceptor for a strong interaction between plecstatin and plectin. Second, time-dependent response profiling experiments provided evidence that plecstatin-2 induced an integrated stress response (ISR) in HCT116 cell culture. The phosphorylation of eIF2a, a key mediator of the ISR, after 3 h treatment indicated that this perturbation was initiated by the intact plecstatin-2 prodrug, while the effects of plectin-targeting are mediated by activated plecstatin-2. Significance to metallomicsCell-level investigations of metallodrugs by shotgun proteomics are still scarce despite the evident advantages of these methods. We performed time-dependent target profiling experiments with organoruthenium-based plecstatins in cell lysates of HCT116 colon carcinoma cells. The changes in target selectivity over time correlated with the activation status of the metallo-prodrug. The target engagement of the plecstatins was tested by substituting a hydrogen bond acceptor with a hydrogen bond donor, which abrogated the plect...

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Cyclometalated Gold(III) Complexes Containing N‐Heterocyclic Carbene Ligands Engage Multiple Anti‐Cancer Molecular Targets

Cited by 35 publications

References 69 publications

New gold pincer-type complexes induce caspase-dependent apoptosis in human cancer cells in vitro

New gold pincer-type complexes induce caspase-dependent apoptosis in human cancer cells in vitro

Gold(III) Complexes for Antitumor Applications: An Overview

Time-dependent shotgun proteomics revealed distinct effects of an organoruthenium prodrug and its activation product on colon carcinoma cells

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