Pharmaco-genomic investigations of organo-iridium anticancer complexes reveal novel mechanism of action

Hearn, Jessica M.; Hughes, George M.; Romero‐Canelón, Isolda; Munro, Alison F.; Rubio‐Ruíz, Belén; Liu, Zhe; Carragher, Neil O.; Sadler, Peter J.

doi:10.1039/c7mt00242d

Cited by 42 publications

(36 citation statements)

References 52 publications

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“…1 RomeroCanelón and Sadler suggested the use of systems pharmacology approaches to assess metallodrug effects in 2015 2 and proteomics [3][4][5][6] or transcriptomics 7,8 approaches are being reported with increasing frequency. Such cell-level investigations are still challenging because metallodrugs are considered to be rather unspecific and the detailed modes of action are indeed elusive in most cases.…”

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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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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“…NPMBC inhibit the growth of TNBC cells better than non-TNBC cells [66]. Furthermore, NPMBC of which effects are dose- [49,53,55,67] and time- [63,67] dependent could be more cytotoxic than platinum-based drugs [52,53,57,58,68]. For example, Biancalana et al [57] observed that ruthenium complexes have good cytotoxic activity, with IC 50 values substantially lower than the values obtained with cisplatin on MDA-MB-231 cells.…”

Section: Suppression Of Cancer Cell Viability In Association With Thementioning

confidence: 99%

“…Furthermore, a study suggests that NPMBC could also inhibit angiogenesis [55]; however, because of scarce evidence, no definitive conclusion can be drawn on the role of these compounds in the regulation of blood vessel formation. In any case, it is thought that NPMBC are frequently multi-targeted and attack different biochemical pathways simultaneously [53,66,68], sometimes in a synergic way [37,62]. Cellular studies constitute an important step in the development of drugs; however, demonstrating efficacy in suitable animal models and validating cellular observations in vivo are a condition sine qua non for clinical trials investigating potential anticancer agents.…”

Section: Anticancer Effects Of Non-platinum Mbc (Npmbc)mentioning

confidence: 99%

“…For example, Biancalana et al [57] observed that ruthenium complexes have good cytotoxic activity, with IC 50 values substantially lower than the values obtained with cisplatin on MDA-MB-231 cells. These differences could be due to the fact that they have different mechanisms of action; for example, the activation of p53-dependent or p53-independent checkpoints by cisplatin or ruthenium complexes, respectively [9,52,54,68]. Since platinum-based drugs and NPMBC act on different pathways, NPMBC could be a new therapeutic option for patients with TNBC resistant to platinum-based drugs.…”

Section: Suppression Of Cancer Cell Viability In Association With Thementioning

confidence: 99%

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Non-Platinum Metal Complexes as Potential Anti-Triple Negative Breast Cancer Agents

et al. 2018

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Breast cancer (BC) is the most common cancer in women worldwide, with a mortality rate that has been forecasted to rise in the next decade. This is especially worrying for people with triple-negative BC (TNBC), because of its unresponsiveness to current therapies. Different drugs to treat TNBC have been assessed, and, although platinum chemotherapy drugs seem to offer some hope, their drawbacks have motivated extensive investigations into alternative metal-based BC therapies. This paper aims to: (i) describe the preliminary in vitro and in vivo anticancer properties of non-platinum metal-based complexes (NPMBC) against TNBC; and (ii) analyze the likely molecular targets involved in their anticancer activity.

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“…However, FDA approved Pt drugs includes only three name (cisplatin, oxaliplatin and carboplatin for cancer chemotherapy, due to inappropriate distribution in cell and inactivation by some cellular mechanism . These open up a great scope for researchers of medicinal inorganic chemistry to design and synthesize metallonuclease agents, which can specifically interact with the tumor cell and damage cellular DNA damage by forming metal‐DNA adduct, and a wide range of transition‐metal based biologically active compounds are currently under consideration for future development …”

Section: Introductionmentioning

confidence: 99%

Spectroscopic and electrochemical study for evaluating DNA interaction activity of 4‐(3‐halophenyl)‐6‐(pyridin‐2‐yl)pyrimidin‐2‐amine based piano stool Cp* Rh (III) and Ir (III) complexes

Vekariya

Karia

Bhatt

et al. 2019

Applied Organom Chemis

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Six novel organometallic half sandwich complexes [(η5‐C5Me5)M(L1–3)Cl]Cl.2H2O were synthesized using [{(η5‐C5Me5)M(μ‐Cl)Cl2], where M = Ir (III)/Rh (III) and L1–3 = three pyridyl pyrimidine based ligands; and characterized by NMR, Infra‐red spectroscopy, conductance, elemental and thermal analysis. The complex‐DNA binding mode and/or strength evaluated using absorption titration, electrochemical studies and hydrodynamic measurement proposed intercalative binding mode, which was also confirmed by molecular docking study. Differential pulse voltammetry and cyclic voltammetry studies indicated an alteration in oxidation and reduction potentials of complexes (M+4/M+3) in presence of CT‐DNA. The metal complexes can cleave plasmid DNA as proposed in gel electrophoretic analysis. The LC50 values of complexes evaluated on brine shrimp suggested their potent cytotoxic nature.

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Pharmaco-genomic investigations of organo-iridium anticancer complexes reveal novel mechanism of action

Abstract: Transcriptomic, phenotypic and high throughput data reveal unique anticancer mechanisms shared by organometallic iridium and osmium complexes.

Cited by 42 publications

References 52 publications

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

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

Non-Platinum Metal Complexes as Potential Anti-Triple Negative Breast Cancer Agents

Spectroscopic and electrochemical study for evaluating DNA interaction activity of 4‐(3‐halophenyl)‐6‐(pyridin‐2‐yl)pyrimidin‐2‐amine based piano stool Cp* Rh (III) and Ir (III) complexes

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