Emerging Protein Targets for Anticancer Metallodrugs: Inhibition of Thioredoxin Reductase and Cathepsin B by Antitumor Ruthenium(II)−Arene Compounds

2008 ◽  
Vol 51 (21) ◽  
pp. 6773-6781 ◽  
Author(s):  
Angela Casini ◽  
Chiara Gabbiani ◽  
Francesca Sorrentino ◽  
Maria Pia Rigobello ◽  
Alberto Bindoli ◽  
...  
Keyword(s):  
Cathepsin B ◽  
Thioredoxin Reductase ◽  
Protein Targets ◽  
Anticancer Metallodrugs

scholarly journals Metalloproteomics for molecular target identification of protein-binding anticancer metallodrugs

Metallomics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1627-1636
Author(s):  
Tasha R. Steel ◽  
Christian G. Hartinger
Keyword(s):  
Protein Binding ◽  
Anticancer Agents ◽  
Target Identification ◽  
Molecular Target ◽  
Protein Targets ◽  
Anticancer Metallodrugs

The development of the metallodrug pull-down as a metalloproteomic technique has enabled the identification of the protein targets of metal-based anticancer agents.

scholarly journals Computational Studies of Au(I) and Au(III) Anticancer MetalLodrugs: A Survey

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7600
Author(s):  
Iogann Tolbatov ◽  
Alessandro Marrone ◽  
Cecilia Coletti ◽  
Nazzareno Re
Keyword(s):  
Glutathione Peroxidase ◽  
Computational Chemistry ◽  
Thioredoxin Reductase ◽  
Organometallic Complexes ◽  
Correct Prediction ◽  
Computational Studies ◽  
Glutathione S Transferase ◽  
Protein Residues ◽  
Antitumor Compounds ◽  
Anticancer Metallodrugs

Owing to the growing hardware capabilities and the enhancing efficacy of computational methodologies, computational chemistry approaches have constantly become more important in the development of novel anticancer metallodrugs. Besides traditional Pt-based drugs, inorganic and organometallic complexes of other transition metals are showing increasing potential in the treatment of cancer. Among them, Au(I)- and Au(III)-based compounds are promising candidates due to the strong affinity of Au(I) cations to cysteine and selenocysteine side chains of the protein residues and to Au(III) complexes being more labile and prone to the reduction to either Au(I) or Au(0) in the physiological milieu. A correct prediction of metal complexes’ properties and of their bonding interactions with potential ligands requires QM computations, usually at the ab initio or DFT level. However, MM, MD, and docking approaches can also give useful information on their binding site on large biomolecular targets, such as proteins or DNA, provided a careful parametrization of the metal force field is employed. In this review, we provide an overview of the recent computational studies of Au(I) and Au(III) antitumor compounds and of their interactions with biomolecular targets, such as sulfur- and selenium-containing enzymes, like glutathione reductases, glutathione peroxidase, glutathione-S-transferase, cysteine protease, thioredoxin reductase and poly (ADP-ribose) polymerase 1.

Thioredoxin reductase, an emerging target for anticancer metallodrugs. Enzyme inhibition by cytotoxic gold(iii) compounds studied with combined mass spectrometry and biochemical assays

MedChemComm ◽  
2011 ◽  
Vol 2 (1) ◽  
pp. 50-54 ◽  
Author(s):  
Chiara Gabbiani ◽  
Guido Mastrobuoni ◽  
Francesca Sorrentino ◽  
Barbara Dani ◽  
Maria Pia Rigobello ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Enzyme Inhibition ◽  
Thioredoxin Reductase ◽  
Biochemical Assays ◽  
Anticancer Metallodrugs

scholarly journals Proteins as possible targets for antitumor metal complexes: biophysical studies of their interactions

2009 ◽  
Author(s):  
Chiara Gabbiani
Keyword(s):  
Mechanism Of Action ◽  
Anticancer Agents ◽  
Protein Adducts ◽  
Functional Information ◽  
X Ray Diffraction ◽  
Protein Targets ◽  
X Ray ◽  
Important Group ◽  
Biophysical Studies ◽  
Anticancer Metallodrugs

There is considerable interest today for the reactions of anticancer metallodrugs with proteins as these interactions might feature processes that are crucial for the biodistribution, the toxicity and even the mechanism of action of this important group of anticancer agents. Valuable structural and functional information on these adducts could be derived from several biophysical studies mainly relying on the application of X-ray diffraction and ESI MS techniques. The structural and functional information achieved on the respective metallodrug–protein adducts allowed us to identify some general trends in the reactivity of anticancer metallodrugs with protein targets.

scholarly journals The Natural Compound Oblongifolin C Exhibits Anticancer Activity by Inhibiting HSPA8 and Cathepsin B In Vitro

2020 ◽  
Vol 11 ◽  
Author(s):  
Li Han ◽  
Danqing Xu ◽  
Zhichao Xi ◽  
Man Wu ◽  
Wan Najbah Nik Nabil ◽  
...  
Keyword(s):  
Heat Shock ◽  
Cancer Cells ◽  
Cathepsin B ◽  
Nuclear Translocation ◽  
A549 Cells ◽  
Titration Calorimetry ◽  
Autophagic Flux ◽  
Protein Targets ◽  
Apoptosis Rate

PPAPs (Polycyclic polyprenylated acylphloroglucinols) are a class of compounds with diverse bioactivities, including anticancer effects. Oblongifolin C (OC) is a PPAP isolated from the plant of Garcinia yunnanensis Hu. We previously discovered that OC induces apoptosis, inhibits autophagic flux, and attenuates metastasis in cancer cells. However, the protein targets and the detailed mechanism of action of OC remain unclear. To identify protein targets of OC, a non-labeled protein fishing assay was performed, and it was found that OC may interact with several proteins, including the heat shock 70 kDa protein 8 (HSPA8). Expanding on our previous studies on protein cathepsin B, this current study applied Surface Plasmon Resonance (SPR) and Isothermal Titration Calorimetry (ITC) to confirm the potential binding affinity between OC and two protein targets. This study highlights the inhibitory effect of OC on HSPA8 in cancer cells under heat shock stress, by specifically inhibiting the translocation of HSPA8. OC also enhanced the interaction between HSPA8, HSP90, and p53, upregulated the expression of p53 and significantly promoted apoptosis in cisplatin-treated cells. Additionally, a flow cytometry assay detected that OC sped up the apoptosis rate in HSPA8 knockdown A549 cells, while overexpression of HSPA8 delayed the OC-induced apoptosis rate. In summary, our results reveal that OC potentially interacts with HSPA8 and cathepsin B and inhibits HSPA8 nuclear translocation and cathepsin B activities, altogether suggesting the potential of OC to be developed as an anticancer drug.

Dicarbonyl derived post-translational modifications: chemistry bridging biology and aging-related disease

2020 ◽  
Vol 64 (1) ◽  
pp. 97-110
Author(s):  
Christian Sibbersen ◽  
Mogens Johannsen
Keyword(s):  
Mass Spectrometry ◽  
Future Research ◽  
Amino Acid Residues ◽  
Post Translational Modification ◽  
Dicarbonyl Compounds ◽  
Protein Targets ◽  
Post Translational Modifications ◽  
Reactive Protein ◽  
Glycation End Products ◽  
Direct Mass Spectrometry

Abstract In living systems, nucleophilic amino acid residues are prone to non-enzymatic post-translational modification by electrophiles. α-Dicarbonyl compounds are a special type of electrophiles that can react irreversibly with lysine, arginine, and cysteine residues via complex mechanisms to form post-translational modifications known as advanced glycation end-products (AGEs). Glyoxal, methylglyoxal, and 3-deoxyglucosone are the major endogenous dicarbonyls, with methylglyoxal being the most well-studied. There are several routes that lead to the formation of dicarbonyl compounds, most originating from glucose and glucose metabolism, such as the non-enzymatic decomposition of glycolytic intermediates and fructosyl amines. Although dicarbonyls are removed continuously mainly via the glyoxalase system, several conditions lead to an increase in dicarbonyl concentration and thereby AGE formation. AGEs have been implicated in diabetes and aging-related diseases, and for this reason the elucidation of their structure as well as protein targets is of great interest. Though the dicarbonyls and reactive protein side chains are of relatively simple nature, the structures of the adducts as well as their mechanism of formation are not that trivial. Furthermore, detection of sites of modification can be demanding and current best practices rely on either direct mass spectrometry or various methods of enrichment based on antibodies or click chemistry followed by mass spectrometry. Future research into the structure of these adducts and protein targets of dicarbonyl compounds may improve the understanding of how the mechanisms of diabetes and aging-related physiological damage occur.

In Search of Novel Cancer Therapeutics: Assessing the NCI Natural Product Library against Ten Anti-Apoptotic Protein Targets

Planta Medica ◽  
2013 ◽  
Vol 79 (10) ◽  
Author(s):  
DB Divlianska ◽  
AE Wright ◽  
S Francis ◽  
MA Walters ◽  
CE Salomon ◽  
...  
Keyword(s):  
Natural Product ◽  
Cancer Therapeutics ◽  
Protein Targets ◽  
Apoptotic Protein ◽  
Natural Product Library
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