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Mitochondrial uncoupling proteins (UCP) are a part of the large family of mitochondrial solute carriers (SLC25s), concentrated in the inner mitochondrial membrane that carries protons from intermembrane space to the matrix. Further, some UCPs are also involved in the transportation of the fatty acid anions and catalyzed the proton transport by fatty acid cycling across the membrane. Out of the 5 UCPs, UCP 2, 4, and 5 are localized in the central nervous system (CNS), and alteration within the expression of these UCPs results in neuronal dysfunction and, ultimately, death of neurons. UCPs play a vital role in regulating mitochondrial membrane potential, preventing reactive oxygen species (ROS) production, alteration in neuronal activity, and the regulation of calcium homeostasis that ultimately results in the prevention of neuronal loss. These changes in mitochondria impact the function and survival of neurons playing a critical role in the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). Additionally, UCP2 regulates the microglia response towards neuroinflammation by modulating microglia's M1 and M2 phenotypes. These microglia cells are further involved in regulating inflammatory response and synaptic functions. Moreover, UCP2, 4, and 5 are ubiquitously present in all brain regions that negatively regulate ROS production and inflammation, leading to the prevention of neuronal cell death. Increased ROS production is a common symptom reported in neurodegenerative diseases that affect several pathways concerned with neuronal death, either apoptosis or autophagy. These accumulating evidence suggested UCPs as a possible therapeutic target for the management of neurodegenerative diseases. Show less

The accumulation of lipid peroxides is recognized as a determinant of the occurrence of ferroptosis. However, the sensors and amplifying process of lipid peroxidation linked to ferroptosis remain obscure. Here we identify PKCβII as a critical contributor of ferroptosis through independent genome-wide CRISPR-Cas9 and kinase inhibitor library screening. Our results show that PKCβII senses the initial lipid peroxides and amplifies lipid peroxidation linked to ferroptosis through phosphorylation and activation of ACSL4. Lipidomics analysis shows that activated ACSL4 catalyses polyunsaturated fatty acid-containing lipid biosynthesis and promotes the accumulation of lipid peroxidation products, leading to ferroptosis. Attenuation of the PKCβII-ACSL4 pathway effectively blocks ferroptosis in vitro and impairs ferroptosis-associated cancer immunotherapy in vivo. Our results identify PKCβII as a sensor of lipid peroxidation, and the lipid peroxidation-PKCβII-ACSL4 positive-feedback axis may provide potential targets for ferroptosis-associated disease treatment. Show less

Solute carrier family 25 (SLC25) encodes transport proteins at the inner mitochondrial membrane and functions as carriers for metabolites. Although SLC25 genetic variants correlate with human metabolic diseases, their roles in colon cancer remain unknown. Cases of colon cancer were retrieved from The Cancer Genome Atlas, and the transcriptionally differentially expressed members (DEMs) of SLC25 were identified. DNA level alterations, clinicopathological characteristics, and clinical survival were also investigated. A risk score model based on the DEMs was constructed to further evaluate their prognostic values in a clinical setting. The results were preliminarily validated using bioinformatic analysis of datasets from the Gene Expression Omnibus, immunohistochemical evaluations in clinical specimens, and functional experiments in colon cancer-derived cell lines. Thirty-seven DEMs were identified among 53 members of SLC25. Eight of 37 DEMs were introduced into a risk score model using integrated LASSO regression and multivariate Cox regression. Validated by GSE395282 and GSE175356, DEMs with high-risk scores were associated with the phenotypes of increasing tumor immune infiltration and decreasing glycolysis and apoptosis contents. SLC25A5 was downregulated in cancer, and its upregulation was related to better overall survival in patients from public datasets and in clinical cases. High SLC25A5 expression was an independent prognostic factor for 79 patients after surgical treatment. A negative correlation between CD8 and SLC25A5 was determined in specimens from 106 patients with advanced colon cancer. SLC25A5 attenuated cell proliferation, upregulated the expression of programmed cell death-related signatures, and exerted its biological function by inhibiting the MAPK signaling pathway. Our study reveals that mitochondrial SLC25 has prognostic value in patients with colon cancer. The bioinformatic analyses by following verification in situ and in vitro provide direction for further functional and mechanistic studies on the identified member of SLC25. Show less

Platinum anticancer drugs inhibit the division of cancer cells through a DNA binding mechanism. The bimetallic platinum compounds have a possibility for blocking DNA replication via the cross-linking of DNA functional groups at different distances. Many compounds with metals of the platinum group have been tested for possible antitumor activity. The main target of their biological action is a DNA molecule. A combined approach to the study of the interaction of DNA with biologically active compounds of this type is proposed. The capabilities of various methods (hydrodynamic, spectral, microscopy) in obtaining information on the type of binding of coordination compounds to DNA are compared. The analysis of DNA binding with platinum binuclear compounds containing pyrazine, tetrazole, 5- methyltetrazole, 3-propanediamine as bridging ligands in a solution was carried out with the methods of circular dichroism (CD), luminescent spectroscopy (LS), low gradient viscometry (LGV), flow birefringence (FB) and atomic force microscopy (AFM). The competitive binding of different platinum compounds to DNA and the analysis of platinum attachment to DNA after protonation of its nitrogen bases simply indicates the involvement of N7 guanine in binding. Fluorescent dye DAPI was also used to recognize the location of platinum compounds in DNA grooves. DNA conformational changes recorded by variations in persistent length, polyelectrolyte swelling, DNA secondary structure, and its stability clarify the molecular mechanism of the biological activity of platinum compounds. Show less

AbstractA phosphine gold(I) and phosphine‐phosphonium gold(I) complexes bearing a fluorescent coumarin moiety were synthesized and characterized. Both complexes displayed interesting photophysical properties: good molar absorption coefficient, good quantum yield of fluorescence, and ability to be tracked in vitro thanks to two‐photon imaging. Their in vitro and in vivo biological properties were evaluated onto cancer cell lines both human and murine and into CT26 tumor‐bearing BALB/c mice. They displayed moderate to strong antiproliferative properties and the phosphine‐phosphonium gold(I) complex induced significant in vivo anti‐cancer effect. TLDR: Both complexes displayed moderate to strong antiproliferative properties and the phosphine‐phosphonium gold(I) complex induced significant in vivo anti‐cancer effect. Show less

Surface determinants newly expressed by apoptotic cells that are involved in triggering potent immunosuppressive responses, referred to as "innate apoptotic immunity (IAI)" have not been characterized fully. It is widely assumed, often implicitly, that phosphatidylserine, a phospholipid normally cloistered in the inner leaflet of cells and externalized specifically during apoptosis, is involved in triggering IAI, just as it plays an essential role in the phagocytic recognition of apoptotic cells. It is notable, however, that the triggering of IAI in responder cells is not dependent on the engulfment of apoptotic cells by those responders. Contact between the responder and the apoptotic target, on the other hand, is necessary to elicit IAI. Previously, we demonstrated that exposure of protease-sensitive determinants on the apoptotic cell surface are essential for initiating IAI responses; exposed glycolytic enzyme molecules were implicated in particular. Here, we report our analysis of the involvement of externalized phosphatidylserine in triggering IAI. To analyze the role of phosphatidylserine, we employed a panel of target cells that either externalized phosphatidylserine constitutively, independently of apoptosis, or did not, as well as their WT parental cells that externalized the phospholipid in an apoptosis-dependent manner. We found that the externalization of phosphatidylserine, which can be fully uncoupled from apoptosis, is neither sufficient nor necessary to trigger the profound immunomodulatory effects of IAI. These results reinforce the view that apoptotic immunomodulation and phagocytosis are dissociable and further underscore the significance of protein determinants localized to the cell surface during apoptosis in triggering innate apoptotic immunity. Show less

AbstractBrain cancer, one of the most lethal diseases, urgently requires the discovery of novel theranostic agents. In this context, molecules based on six‐membered phosphorus heterocycles – phosphaphenalenes – are especially attractive; they possess unique characteristics that allow precise chemical engineering. Herein, we demonstrate that subtle structural modifications of the phosphaphenalene‐based gold(I) complexes lead to modify their electronic distribution, endow them with marked photophysical properties and enhance their efficacy against cancer. In particular, phosphaphenalene‐based gold(I) complexes containing a pyrrole ring show antiproliferative properties in 14 cell lines including glioblastomas, brain metastases, meningiomas, IDH‐mutant gliomas and head and neck cancers, reaching IC50 values as low as 0.73 μM. The bioactivity of this new family of drugs in combination with their photophysical properties thus offer new research possibilities for both the fundamental investigation and treatment of brain cancer. Show less

Lipid-conjugated Ru(III) complexes - designed to obtain lipophilic analogues of the low molecular weight derivative AziRu, which is a NAMI-A-like anticancer agent - have been synthesized and fully characterized. A detailed biophysical investigation, including multiple, integrated techniques, allowed determining their molecular and self-assembling properties in aqueous solutions mimicking the extracellular environment, showing that our design produced a protective effect from hydrolysis of the Ru(III) complexes. In vitro biological experiments, carried out in comparison with AziRu, demonstrated that, among the novel lipophilic Ru(III) complexes synthesized, the compounds derivatized with palmitic and stearic acid, that we named PalmiPyRu and StePyRu respectively, showed attractive features and a promising antiproliferative activity, selective on specific breast cancer phenotypes. To get a deeper insight into their interactions with potential biomacromolecular targets, their ability to bind both bovine serum albumin (BSA), an abundant serum carrier protein, and some DNA model systems, including duplex and G-quadruplex structures, has been investigated by spectroscopic techniques. Inductively coupled plasma-mass spectrometry (ICP-MS) analysis of the ruthenium amount incorporated in human MCF-7 and MDA-MB-231 breast cancer cells, after incubation in parallel experiments with PalmiPyRu and AziRu, showed a markedly higher cell uptake of the lipophilic Ru(III) complex with respect to AziRu. These data confirmed that the proper lipidic tail decorating the metal complex not only favoured the formation of aggregates in the extracellular media but also improved their cell membrane penetration, thus leading to higher antiproliferative activity selective on breast cancer cells. Show less

Three iridium (III) polypyridine complexes [Ir(bzq)₂(maip)](PF₆) (Ir1，bzq = benzo[h]quinoline, maip = 3-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(bzq)₂(apip)](PF₆) (Ir2, apip = 2-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(bzq)₂(paip)](PF₆) (Ir3, paip = 4-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized. The cytotoxic activities of the three complexes against human osteosarcoma HOS, U2OS, MG63 and normal LO2 cells were evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method. The results showed that Ir1-3 exhibited moderate antitumor activity against HOS with IC₅₀ of 21.8 ± 0. 4 μM,10.5 ± 1.8 μM and 7.4 ± 0.4 μM, respectively. We found that Ir1-3 can effectively inhibit HOS cells growth and blocked the cell cycle at the G0/G1 phase. Further studies revealed that complexes can increase intracellular reactive oxygen species (ROS) and Ca²⁺, which accompanied by mitochondria-mediated intrinsic apoptosis pathway. In addition, autophagy was also investigated. Taken together, the complexes induce HOS apoptosis through a ROS-mediated mitochondrial dysfunction pathway and inhibition of the PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) signaling pathway. This study provides useful help for understanding the anticancer mechanism of iridium (III) complexes toward osteosarcoma treatment. Show less

Transition metal coordination complexes have provided cancer treatment with new insights to overcome the limitations of current chemotherapeutic agents. Utilization of bifunctional tetrazole–carboxylate ligands with Zn(II) obtained two self-assembled complexes [Zn(HL1)(bipy)3/2(H2O)]·CH3OH·4(H2O) (1) (H3L1 = 1,3,5-tri(2-carboxymethyltetrazol-5-yl) benzene) and [Zn(L2)2(H2O)2]2·2H2O (2) (HL2 = (5-pyridin-3-yl-tetrazol-2-yl)-acetic acid). The X-ray diffraction results showed that the two complexes displayed a two-dimensional (2D) layer structure and a one-dimensional (1D) layer structure. Nanocoprecipitation with DSPE-PEG-2000 resulted in the formation of complex nanoparticles (NPS) with excellent water dispersion. In vitro CCK-8 assay indicated the two NPs exert high cytotoxicity and sensitivity and a low half-maximum inhibitory concentration (IC50) towards HeLa than HepG2 cells. In addition, the cytotoxicity was also confirmed by live/dead co-stained experiments. The presented experimental results showed the 1 and 2 NPs were capable of inhibiting cell proliferation in vitro and may help design coordination complex-based anticancer candidates for cancer cells. Show less

The field of oxygen free radicals, antioxidants and reactive oxygen species (ROS) has exploded in the past few decades, and BBRC has published several seminal papers. ROS can cause oxidative damage, but also play fundamental roles in living organisms, in such processes as signal transduction and defence against pathogens. ROS underpin every aspect of human biology. Indeed, an endless stream of published papers refers to the biological roles of "ROS". Sadly, much of this work is mechanistically meaningless. To make progress, the detailed molecular mechanisms of action of ROS must be elucidated and appropriate methodology must be used to measure them and the oxidative damage that they can cause, as emphasized in a recent review by Murphy et al. Attention must also switch from clinical studies involving administration of high-dose supplements of vitamins E, C and β-carotene for the treatment or prevention of human disease into other promising diet-derived cytoprotective agents. One of them may be ergothioneine. Show less

Tetrazolato-bridged dinuclear platinum(II) complexes ([{cis-Pt(NH₃)₂}₂(μ-OH)(μ-5-R-tetrazolato-N2,N3)]²⁺; tetrazolato-bridged complexes) show remarkable cytotoxic effects in vitro and antitumor activity in vivo. Here, we examined the structure-activity relationship of a series of fluorine-containing derivatives (R = CFH₂, CF₂H, or CF₃), focusing on their lipophilicity, cellular accumulation, cytotoxicity, interactions with a nucleobase and double-stranded deoxyribonucleic acid, and in vivo antitumor efficacy. Fluorination had a little effect on the properties of the derivatives in vitro; however, marked differences in in vitro cytotoxicity and in vivo tumor growth inhibition activity were observed. In BALB/c mice bearing colon-26 tumors, the antitumor efficacies of the derivatives were markedly altered, even by changing the number of fluorine atoms by one. In addition, one derivative, [{cis-Pt(NH₃)₂}₂(μ-OH)(μ-5-difluoromethyltetrazolato-N2,N3)](NO₃)₂, showed a significantly higher antitumor efficacy compared with oxaliplatin, a current first-line drug and the only platinum-based drug approved for the treatment of colon cancer. Together, the present results indicate that introducing fluorine into tetrazolato-bridged complexes may be useful for modulating in vivo activities. Show less

In this work, we report on the development of fluorescent half-sandwich iridium complexes using a fluorophore attachment strategy. These constructs consist of pentamethylcyclopentadienyl (Cp*) iridium units ligated by picolinamidate donors conjugated to green-emitting boron-dipyrromethene (bodipy) dyes. Reaction studies in H₂O/THF mixtures showed that the fluorescent Ir complexes were active as catalysts for transfer hydrogenation, with activities similar to that of their non-fluorescent counterparts. The iridium complexes were taken up by NIH-3T3 mouse fibroblast cells, with 50% inhibition concentrations ranging from ~20-70 μM after exposure for 3 h. Visualization of the bodipy-functionalized Ir complexes in cells using fluorescence microscopy revealed that they were localized in the mitochondria and lysosome but not the nucleus. These results indicate that our fluorescent iridium complexes could be useful for future biological studies requiring intracellular catalyst tracking. Show less

In eukaryotes, three RNA polymerases (RNAPs) play essential roles in the synthesis of various types of RNA: namely, RNAPI for rRNA; RNAPII for mRNA and most snRNAs; and RNAPIII for tRNA and other small RNAs. All three RNAPs possess a short flexible tail derived from their common subunit RPB6. However, the function of this shared N-terminal tail (NTT) is not clear. Here we show that NTT interacts with the PH domain (PH-D) of the p62 subunit of the general transcription/repair factor TFIIH, and present the structures of RPB6 unbound and bound to PH-D by nuclear magnetic resonance (NMR). Using available cryo-EM structures, we modelled the activated elongation complex of RNAPII bound to TFIIH. We also provide evidence that the recruitment of TFIIH to transcription sites through the p62-RPB6 interaction is a common mechanism for transcription-coupled nucleotide excision repair (TC-NER) of RNAPI- and RNAPII-transcribed genes. Moreover, point mutations in the RPB6 NTT cause a significant reduction in transcription of RNAPI-, RNAPII- and RNAPIII-transcribed genes. These and other results show that the p62-RPB6 interaction plays multiple roles in transcription, TC-NER, and cell proliferation, suggesting that TFIIH is engaged in all RNAP systems. Show less

Title: Ru(III) complexes with pyrazolopyrimidines as anticancer agents: bioactivities and the underlying mechanisms. Abstract: Three ruthenium(III) complexes with pyrazolopyrimidine [Ru(Ln)(H2O)Cl3] (1-3, n = 1-3) were prepared and characterized. These Ru(III) compounds show strong cytotoxicity against six cancer cell lines and low toxicity to normal human liver cells. Particularly, they exhibited stronger cytotoxicity to SK-OV-3 cells than cisplatin. Mechanism studies revealed that complex 1 inhibited tumor cell invasion and suppressed cell proliferation, induced apoptosis by elevating the levels of intracellular ROS (reactive oxygen species) and free calcium (Ca2+), and reduced mitochondrial membrane potential (ΔΨ). It also activated the caspase cascade, accompanied with upregulation of cytochrome c, Bax, p53, Apaf-1 and downregulation of Bcl-2. Moreover, complex 1 caused cell cycle arrest at S phase by inhibiting the expression of CDC 25, cyclin A2 and CDK 2 proteins, and induced DNA damage by interacting with DNA and inhibiting the topoisomerase I enzyme. Complex 1 exhibited efficient in vivo anticancer activity in a model of SK-OV-3 tumor xenograft. Show less

Cancer is the deadliest disease in the world behind heart disease. Sadly, this remains true even as we suffer the ravages of the Covid-19 pandemic. Whilst current chemo- and radiotherapeutic treatment strategies have significantly improved the patient survival rate, disease reoccurrence continues to pose a deadly risk for all too many patients. Incomplete removal of tumour cells from the body increases the chances of metastasis and developing resistance against current treatments. Immunotherapy represents a therapeutic modality that has helped to overcome these limitations in recent decades. However, further progress is needed. So-called immunogenic cell death (ICD) is a recently discovered and unique mode of cell death that could trigger this necessary further progress. ICD involves stimulation of a tumour-specific immune response as a downstream effect. Facilitated by certain treatment modalities, cells undergoing ICD can trigger the IFN-γ mediated immune response involving cytotoxic T cells (CTLs) and γδ T cells that eradicate residual tumour cells. In recent years, there has been a significant increase in the number of small-molecules being tested as potential ICD inducers. A large number of these ICD inducers are metal-based complexes. In fact, anticancer metal drugs based on Pt, Ru, Ir, Cu, and Au are now known to give rise to an immune response against tumour cells as the result of ICD. Advances have also been made in terms of exploiting combinatorial and delivery strategies. In favourable cases, these approaches have been shown to increase the efficacy of otherwise ICD "silent" metal complexes. Taken in concert, rationally designed novel anticancer metal complexes that can act as ICD inducers show promise as potential new immunotherapies for neoplastic disease. This Tutorial Review will allow the readers to assess the progress in this fast-evolving field thus setting the stage for future advances. Show less

Biguanides are a family of antidiabetic drugs with documented anticancer properties in preclinical and clinical settings. Despite intensive investigation, how they exert their therapeutic effects is still debated. Many studies support the hypothesis that biguanides inhibit mitochondrial complex I, inducing energy stress and activating compensatory responses mediated by energy sensors. However, a major concern related to this "complex" model is that the therapeutic concentrations of biguanides found in the blood and tissues are much lower than the doses required to inhibit complex I, suggesting the involvement of additional mechanisms. This comprehensive review illustrates the current knowledge of pharmacokinetics, receptors, sensors, intracellular alterations, and the mechanism of action of biguanides in diabetes and cancer. The conditions of usage and variables affecting the response to these drugs, the effect on the immune system and microbiota, as well as the results from the most relevant clinical trials in cancer are also discussed. Show less

Acute inflammation or resolved inflammation is an adaptive host defense mechanism and is self-limiting, which returns the body to a state of homeostasis. However, unresolved, uncontrolled, or chronic inflammation may lead to various maladies, including cancer. Important evidence that links inflammation and cancer is that nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, reduce the risk and mortality from many cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug developmental work focusing on cyclooxygenase (COX) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in the colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, NSAIDs do not require the presence of COX-2 to prevent cancer. In this review, we highlight the effects of NSAIDs and selective COX-2 inhibitors (COXIBs) on targets beyond COX-2 that have shown to be important against many cancers. Finally, we hone in on specialized pro-resolving mediators (SPMs) that are biosynthesized locally and, in a time, -dependent manner to promote the resolution of inflammation and subsequent tissue healing. Different classes of SPMs are reviewed, highlighting aspirin's potential in triggering the production of these resolution-promoting mediators (resolvins, lipoxins, protectins, and maresins), which show promise in inhibiting cancer growth and metastasis. Show less

For the first time, we herein report on the syntheses of two new Ru(II)/bipyridine/phenanthroline complexes containing lapachol as ligand: complex (1), [Ru (bipy)₂(Lap)]PF₆ and complex (2), [Ru(Lap)(phen)₂]PF₆, where bipy = 2,2'-bipyridine and ph en = 1,10-phenanthroline; Lap = lapachol (2-hydroxy-3-(3-methylbut-2-en-1- yl)naphthalene-1,4-dione). The complexes were synthesized and characterized by elemental analyses, molar conductivity, mass spectrometry, ultraviolet-visible and infrared spectroscopies, nuclear magnetic resonance (¹H, ¹³C), and single crystal X-ray diffraction, for complex (2). In addition, in vitro cytotoxicity was tested against six cancer cells: A549 (lung carcinoma); DU-145 (human prostate carcinoma); HepG2 (human hepatocellular carcinoma), PC-3 (human prostate adenocarcinoma); MDA-MB-231 (human breast adenocarcinoma); Caco-2 (human colorectal adenocarcinoma), and against two non-cancer cells, FGH (human gingival normal fibroblasts) and PNT-2 (prostate epithelial cells). Complex (1) was slightly more toxic and selective than complex (2) for all cell lines, except against the A549 cells, where (2) was more potent than complex (1). The complexes induced an increase in the reactive oxygen species, and the co-treatment with N-acetyl-L-cysteine remarkably suppressed the ROS generation and prevented the reduction of cell viability, suggesting that the cytotoxicity of the complexes is related to the ROS-mediated pathway. Further studies indicated that the complexes may bind to DNA via minor groove interaction. Our studies also revealed that free Lap induces gene mutations in Salmonella Typhimurium, nevertheless, the complexes demonstrated the absence of genotoxicity by the Ames test. The present study provides a relevant contribution to understanding the anti-cancer potential and genetic toxicological events of new ruthenium complexes containing the lapachol molecule as a ligand. Show less

The clinical application of photodynamic therapy is hindered by the high glutathione concentration, poor cancer-targeting properties, poor drug loading into delivery systems, and an inefficient activation of the cell death machinery in cancer cells. To overcome these limitations, herein, the formulation of a promising Ir^III complex into a biodegradable coordination polymer (IrS NPs) is presented. The nanoparticles were found to remain stable under physiological conditions but deplete glutathione and disintegrate into the monomeric metal complexes in the tumor microenvironment, causing an enhanced therapeutic effect. The nanoparticles were found to selectively accumulate in the mitochondria where these trigger cell death by hybrid apoptosis and ferroptosis pathways through the photoinduced production of singlet oxygen and superoxide anion radicals. This study presents the first example of a coordination polymer that can efficiently cause cancer cell death by apoptosis and ferroptosis upon irradiation, providing an innovative approach for cancer therapy. Show less

Quantifying the content of metal-based anticancer drugs within single cancer cells remains a challenge. Here, we used single-cell inductively coupled plasma mass spectrometry to study the uptake and retention of mononuclear (Ir1) and dinuclear (Ir2) Ir^III photoredox catalysts. This method allowed rapid and precise quantification of the drug in individual cancer cells. Importantly, Ir2 showed a significant synergism but not an additive effect for NAD(P)H photocatalytic oxidation. The lysosome-targeting Ir2 showed low dark toxicity in vitro and in vivo. Ir2 exhibited high photocatalytic therapeutic efficiency at 525 nm with an excellent photo-index in vitro and in tumor-bearing mice model. Interestingly, the photocatalytic anticancer profile of the dinuclear Ir2 was much better than the mononuclear Ir1, indicating for the first time that dinuclear metal-based photocatalysts can be applied for photocatalytic anticancer treatment. Show less

AbstractAuranofin is an oral gold(I) compound, initially developed for the treatment of rheumatoid arthritis. Currently, Auranofin is under investigation for oncological application within a drug repurposing plan due to the relevant antineoplastic activity observed both in vitro and in vivo tumor models. In this review, we analysed studies in which Auranofin was used as a single drug or in combination with other molecules to enhance their anticancer activity or to overcome chemoresistance. The analysis of different targets/pathways affected by this drug in different cancer types has allowed us to highlight several interesting targets and effects of Auranofin besides the already well‐known inhibition of thioredoxin reductase. Among these targets, inhibitory‐κB kinase, deubiquitinates, protein kinase C iota have been frequently suggested. To rationalize the effects of Auranofin by a system biology‐like approach, we exploited transcriptomic data obtained from a wide range of cell models, extrapolating the data deposited in the Connectivity Maps website and we attempted to provide a general conclusion and discussed the major points that need further investigation. Show less

Title: Cytotoxic properties of rhenium(I) tricarbonyl complexes of N-heterocyclic carbene ligands. Abstract: A family of eight rhenium(I) tricarbonyl complexes bearing pyridyl-imidazolylidene or bis-imidazolylidene ligands in combination with a series of N-acetyl amino acids ligands (glycine, isoleucine, and proline) and an acetate have been synthesised and characterised. These complexes are of interest as potential anticancer agents, where the oxygen bound carboxylate ligand can exchange with water giving rise to cytotoxic cationic complexes. The pseudo-first-order aquation rate constants for the complexes were evaluated using 1H NMR time-course experiments and for the complexes of the bis-imidazolylidene ligand the average k1 value was 6.22 × 10-5 s-1 while for the pyridyl-imidazolylidene ligand the aquation rate was slower with the average k1 value being 3.00 × 10-5 s-1. Cytotoxicity studies in three cancer cell lines (MDA-MB-231, PC3 and HEPG2) showed that the Re(I) complexes of the bis-imidazolylidene ligand were significantly more toxic than those of the pyridyl-imidazolylidene ligand. Show less

Photoreactive Ru(II) complexes capable of ejecting ligands have been used extensively for photocaging applications and for the creation of "photocisplatin" reagents. The incorporation of distortion into the structure of the coordination complex lowers the energy of dissociative excited states, increasing the yield of the photosubstitution reaction. While steric clash between ligands induced by adding substituents at the coordinating face of the ligand has been extensively utilized, a lesser known, more subtle approach is to distort the coordination sphere by altering the chelate ring size. Here a systematic study was performed to alter metal-ligand bond lengths, angles, and to cause intraligand distortion by introducing a "linker" atom or group between two pyridine rings. The synthesis, photochemistry, and photobiology of five Ru(II) complexes containing CH₂, NH, O, and S-linked dipyridine ligands was investigated. All systems where stable in the dark, and three of the five were photochemically active in buffer. While a clear periodic trend was not observed, this study lays the foundation for the creation of photoactive systems utilizing an alternative type of distortion to facilitate photosubstitution reactions. Show less