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The chemical structure of two-plex tandem mass tag (TMT) reagents. This figure is adapted from reference [58].
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The discovery of the anticancer activity of cisplatin and its clinical application has opened a new field for studying metal-coordinated anticancer drugs. Metal-based anticancer drugs, such as cisplatin, can be transported to cells after entering into the human body and form metal–DNA or metal–protein adducts. Then, responding proteins will recogni...
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... order to solve the shortcomings of the ICAT reagent, Thompson et al. synthesized TMT (tandem mass tags) reagent. The chemical structure of the commercial TMT agent is shown in Figure 7. It consists of a mass reporter region, a cleavable linker region, a mass normalization region, and a reactive group. ...
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The importance of essential metal ions and their metal complexes in the creation of prospective medical therapies has long been recognized. In chemistry, molecular biology, and medicinal fields; the interaction of metal complexes with DNA has been a subject of study. The dithiocarbamate essential metal complex is described extensively in the litera...
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... Label-free techniques are capable of detecting the transient interactions of drug candidates with potential protein targets and globally assessing drug-altered temperature and the proteolytic or chemical stability of proteins, and otherwise do not require synthetic modification of the drug [72,73]. encompass the protein stability based on the oxidation rate (SPROX), [68] pulse proteolysis (PP) [69], drug affinity responsive target stability (DARTS) [70], and limited proteolysis-coupled mass spectrometry (LiP-MS) [71]. ...
... However, to our knowledge, no work has been published. Label-free techniques are capable of detecting the transient interactions of drug candidates with potential protein targets and globally assessing drug-altered temperature and the proteolytic or chemical stability of proteins, and otherwise do not require synthetic modification of the drug [72,73]. ...
Metals are indispensable for the life of all organisms, and their dysregulation leads to various disorders due to the disruption of their homeostasis. Nowadays, various transition metals are used in pharmaceutical products as diagnostic and therapeutic agents because their electronic structure allows them to adjust the properties of molecules differently from organic molecules. Therefore, interest in the study of metal–drug complexes from different aspects has been aroused, and numerous approaches have been developed to characterize, activate, deliver, and clarify molecular mechanisms. The integration of these different approaches, ranging from chemoproteomics to nanoparticle systems and various activation strategies, enables the understanding of the cellular responses to metal drugs, which may form the basis for the development of new drugs and/or the modification of currently used drugs. The purpose of this review is to briefly summarize the recent advances in this field by describing the technological platforms and their potential applications for identifying protein targets for discovering the mechanisms of action of metallodrugs and improving their efficiency during delivery.
... Label-free techniques are able to detect transient interactions of drug candidates with potential protein targets, globally evaluating the temperature altered by the drug, and proteolytic or chemical stability of proteins and otherwise require no synthetic modification of the drug [67], [68]. ...
Metals are indispensable in the life of all organisms, in fact, their dysregulation causes various disorders caused by an interruption of their homeostasis. Nowadays different transition metals are incorporated into pharmaceutical products as diagnostic and therapeutic agents because of their electronic structure which gives them versatility in terms of tuning molecule properties, differently from organic molecules. Hence the interest in the study of metal-drug complexes from different points of view was born and many approaches were developed for the characterization, activation, delivery and molecular mechanisms clarification. The integration of these different approaches starting from chemoproteomics passing through nanoparticle systems to different activation strategies allows the understanding of the cellular responses of metallic drugs, which can be the basis for the design of new drugs and/or modification of drugs currently in use. This review aims to briefly summarize the recent advances in this area by describing the technological platforms and their possible applications to identify protein targets for discovering the mechanisms of action of metallodrugs, and to improve their efficiency in terms of administration.
... When used as adjuvants, they can also improve the effectiveness of antiviral drugs and vaccines [61]. Anticancer metal-based drugs can act via metal-DNA or metal-protein adducts formation (thus, through a genomic or non-genomic target), then activating specific mechanisms leading to cancer cell death [62][63][64]. ...
Nucleoside analogues (NAs) are a family of compounds which include a variety of purine and pyrimidine derivatives, widely used as anticancer and antiviral agents. For their ability to compete with physiological nucleosides, NAs act as antimetabolites exerting their activity by interfering with the synthesis of nucleic acids. Much progress in the comprehension of their molecular mechanisms has been made, including providing new strategies for potentiating anticancer/antiviral activity. Among these strategies, new platinum-NAs showing a good potential to improve the therapeutic indices of NAs have been synthesized and studied. This short review aims to describe the properties and future perspectives of platinum-NAs, proposing these complexes as a new class of antimetabolites.
... In recent years, mass spectrometry-based proteomics has become a powerful and systematic tool for large-scale protein identification of metal-based anti-cancer drug mechanisms and the associated drugprotein interactions [33,34]. In this frame, a few proteomic studies have been carried out so far to unveil the anti-cancer mode of action of AF. ...
... This conclusion underlines the importance of the simultaneous monitoring of protein level and individual Cys redox event extent. Globally, compared to previous proteomics studies [33][34][35][36][37][38][39], our results offer a comprehensive vision of the biochemical aspects of AF cytotoxicity covering a larger number of molecular pathways. ...
The effects of Auranofin (AF) on protein expression and protein oxidation in A2780 cancer cells were investigated through a strategy based on simultaneous expression proteomics and redox proteomics determinations. Bioinformatics analysis of the proteomics data supports the view that the most critical cellular changes elicited by AF treatment consist of thioredoxin reductase inhibition, alteration of the cell redox state, impairment of the mitochondrial functions, metabolic changes associated with conversion to a glycolytic phenotype, induction of ER stress. The occurrence of the above cellular changes was extensively validated by performing direct biochemical assays. Our data are consistent with the concept that AF produces its effects through a multitarget mechanism that mainly affects the redox metabolism and the mitochondrial functions and results into severe ER stress. Results are discussed in the context of the current mechanistic knowledge existing on AF.
... [15][16][17][18][19] Investigating the nuclease activity of small molecules help in elucidating their mechanism of action. 20 Thus, this manuscript focuses on the synthesis of two new 3-formyl indole thiocarbohydrazone ligands and their Cu(II) complexes. The compounds are characterized by IR, NMR, UV-Visible, fluorescence, EPR and mass spectroscopy. ...
Two Schiff base ligands FT1 and FT2 and their Cu(II) complexes were synthesized and characterized by 1H NMR, ESI-MS, IR, UV-Visible, Fluorescence spectroscopy, EPR and single-crystal X-ray diffraction studies. FT1 crystallizes in the triclinic system while FT2 in the orthorhombic. The DNA cleavage activity of Cu(II) complexes was studied using plasmid pBR322 DNA by gel electrophoresis. All compounds cleave DNA on photoirradiation by oxidative mechanism. Two Schiff base ligands FT1 and FT2 and their Cu(II) complexes were synthesized and characterized by 1H NMR, ESI-MS, IR, UV-Visible, Fluorescence spectroscopy, EPR and single-crystal X-ray diffraction studies. Both the Cu(II) complexes of indole thiocarbohydrazones are shown to cleave plasmid pBR322 DNA by oxidative mechanism.
... 3,4 However, there is now substantial evidence that some of these next-generation metal-based compounds have non-conventional modes of action, which excludes DNA-targeting. 8,[11][12][13][14][15] For example, NKP-1339 was found to be a first-in-class GRP78 modulator. 5 Furthermore, we were recently able to validate plectin-targeting for [chlorido(Z 6 -p-cymene)(N-fluorophenyl-2-pyridinecarbothioamide) ruthenium(II)] chloride, termed plecstatin-1 (Scheme 1). ...
Organometallic metal(arene) anticancer agents were believed to confer low selectivity for potential cellular targets. However, the ruthenium(arene) pyridinecarbothioamide (plecstatin-1) showed target selectivity for plectin, a scaffold protein and cytolinker. We employed a three-dimensional cancer spheroid model and showed that plecstatin-1 limited spheroid growth, induced changes in the morphology and in the architecture of tumour spheroids by disrupting the cytoskeletal organization. Additionally, we demonstrated that plecstatin-1 induced oxidative stress, followed by the induction of an immunogenic cell death signature through phosphorylation of eIF2a, exposure of calreticulin, HSP90 and HSP70 on the cell membrane and secretion of ATP followed by release of high mobility group box-1. Significance to metallomics Our work highlights the anticancer effects of plecstatin-1, an organoruthenium drug candidate that selectively targets plectin, in tumour spheroids. The treatment with plecstatin-1 resulted in the expected disruption of the cytoskeleton and phosphorylation of the stress marker eIF2a. This was accompanied by the induction of an immunogenic cell death signature, including calreticulin, high mobility group protein B and extracellular ATP. Thus, together with oxaliplatin and KP1339, plecstatin-1 is among the few metallodrugs that induces an immunogenic cell death signature in vitro and add additional evidence of the promise of metallodrugs in modulating immunogenic mechanisms as an anticancer strategy.
... For the currently used metal-based drugs such as cisplatin, the mode of action of these drugs is thought to involve the formation of DNA-metal or protein-metal adducts after being transported to the cells. Consequently, this leads to the formation of a stable complex after a responding protein recognizes these adducts [87]. However, most Pt(II) based complexes with exchangeable and labile ligands in the cis geometry interact with cellular biomolecules containing glutathione and metallothionein which deactivates these complexes before reaching the targeted site, the DNA [88,89]. ...
... During this process of transportation within the body, the low concentration of the intracellular Clinduces the hydrolysis of this Pt drug (becomes positively charged), making it electrostatically attracted to DNA (negatively charged) [90]. This attraction to the DNA then leads to the formation of DNA intra-strand crosslinks, inter-strand cross-linking and DNA protein cross-linking, which all affect DNA strand synthesis and ultimately causes the death of the cell [87]. The use of these Pt based compounds, however good they may seem, is not without side effects such as myelosuppression, gastrotoxicity, and allergic reactions [91]. ...
The prevalence of infectious diseases, the generation of harmful products such as reactive oxygen species (ROS)
and free radicals within the human body system have created the impetus for innovative research. There is,
therefore, dire need for the continuous discovery of useful medicinal compounds capable of alleviating these
problems. The understanding of the mechanisms of action of potential biological relevant compounds is vital in
the advancement of this area of research. The mechanism of action of most compounds has been increasingly
used to drive the discovery of many useful processes in recent times. In most biological systems, the mechanism
of action of metal complexes has shown to be influenced by the ability of the ligand to control the reactivity of
the metal. This is because the ligands play a role in determining the nature of the secondary coordination sphere
involved in the recognition of biological sites such as DNA, enzymes, and proteins. Ligands, such as dithio-
carbamate, are highly potent and are involved in synergistic activities with the central metal ions of coordination
compounds and also modulate the often-associated toxicity of the metals, whilst their biological properties are
enhanced. Dithiocarbamates have specifically become very useful biological agents due to their compatibility
with most biological systems and the ability to form stable complexes with a different metals. This has resulted in
a wide range of useful biological applications. Hence, this review explores the interaction of dithiocarbamates
with biological systems, their modes of action and mechanism of the process when used as antimicrobial, an-
tioxidant, anticancer and antileishmanial agents.
... Fluorescence from metabolic co-enzymes NAD(P)H and FAD have been used to quantify dynamic changes in tumor cell metabolism [8][9][10][11][12] as an early marker of drug efficacy in vivo and in organoids [13][14][15]. The redox ratio, defined as the fluorescence intensity of NAD(P)H divided by the fluorescence intensity of FAD, is a well-studied metric of electron transfer rate and metabolic activity that does not require exogenous stains or dyes [16][17][18][19][20]. Notably, redox imaging is not amenable to resolving mechanisms of drug action but it can be combined with complementary measures such as proteomics, genomic sequencing, or metabolomics to resolve these mechanisms [21][22][23]. The fluorescence from NAD(P)H is indistinguishable from that of NADH, and will be referred to collectively as NAD(P)H. ...
High-throughput drug screening of patient-derived organoids offers an attractive platform to determine cancer treatment efficacy. Here, selective plane illumination microscopy (SPIM) was used to determine treatment response in organoids with endogenous fluorescence from the metabolic coenzymes NAD(P)H and FAD. Rapid 3-D autofluorescence imaging of colorectal cancer organoids was achieved. A quantitative image analysis approach was developed to segment each organoid and quantify changes in endogenous fluorescence caused by treatment. Quantitative analysis of SPIM volumes confirmed the sensitivity of patient-derived organoids to standard therapies. This proof-of-principle study demonstrates that SPIM is a powerful tool for high-throughput screening of organoid treatment response.
... DNA-damaging drugs operate by directly targeting to DNA. For instance, doxorubicin is able to intercalate the DNA via its insertion between the planar DNA base pairs [58] whereas cisplatin binds to and cross-links DNA which affects DNA strand synthesis and replication [59]. On the other hand, U94 is able to inhibit the DNA repair mechanisms at gene level by downmodulating the transcription of genes specifically involved in DNA damage repair. ...
Triple-negative breast cancer (TNBC) accounts for 15–20% of all breast cancers. In spite of initial good response to chemotherapy, the prognosis of TNBC remains poor and no effective specific targeted therapy is readily available. Recently, we demonstrated the ability of U94, the latency gene of human herpes virus 6 (HHV-6), to interfere with proliferation and with crucial steps of the metastatic cascade by using MDA-MB 231 TNBC breast cancer cell line. U94 expression was also associated with a partial mesenchymal-to-epithelial transition (MET) of cells, which displayed a less aggressive phenotype. In this study, we show the ability of U94 to exert its anticancer activity on three different TNBC cell lines by inhibiting DNA damage repair genes, cell cycle and eventually leading to cell death following activation of the intrinsic apoptotic pathway. Interestingly, we found that U94 acted synergistically with DNA-damaging drugs. Overall, we provide evidence that U94 is able to combat tumor cells with different mechanisms, thus attesting for the great potential of this molecule as a multi-target drug in cancer therapy.
... Due to the adverse effects and acquired resistance of these drugs, efforts have been made to exploit novel anticancer metallodrugs and unveil the molecular mechanism of anticancer activity and drug resistance. The article by Jia and co-workers [9] is focused on the identification, by MS-based quantitative strategies, of proteins which specifically respond or bind to metal-based anticancer drugs and on the elucidation of their mechanisms of action. ...
The term “Proteomics” refers to the characterization of the proteome, that is, all proteins present in a biological system [...]
