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Several PI3K pathway inhibitors are currently approved as cancer treatments; however, finding an acceptable therapeutic window to target this key signalling cascade linking cancer growth with metabolism has proven challenging and the clinical results to date have arguably been disappointing. In this Review, Vasan and Cantley discuss the effects of PI3K pathway alterations on signalling and metabolism in solid tumours as well as past and present efforts to improve the somewhat limited clinical efficacy of PI3K pathway inhibitors, with a particular focus on PI3Kα in breast cancers. Show less

Two Zn(ii) complexes based on tetrazol were prepared. Nanoparticles of the complexes can inhibit the proliferation of cancer cells in vitro. This work provided a strategy on designing anticancer materials based on coordination complexes. Show less

Besides their main function for energy production in form of ATP in processes of oxidative phosphorylation (OxPhos), mitochondria perform many other important cellular functions and participate in various physiological processes that are congregated. For example, mitochondria are considered to be one of the main sources of reactive oxygen species (ROS) and therefore they actively participate in the regulation of cellular redox and ROS signaling. These organelles also play a crucial role in Ca²⁺ signaling and homeostasis. The mitochondrial OxPhos and their cellular functions are strongly cell/tissue specific and can be heterogeneous even within the same cell, due to the existence of mitochondrial subpopulations with distinct functional and structural properties. However, the interplay between different functions of mitochondria is not fully understood. The mitochondrial functions may change as a response to the changes in the cellular metabolism (signaling in). On the other hand, several factors and feedback signals from mitochondria may influence the entire cell physiology (signaling out). Numerous interactions between mitochondria and the rest of cell, various cytoskeletal proteins, endoplasmic reticulum (ER) and other cellular elements have been demonstrated, and these interactions could actively participate in the regulation of mitochondrial and cellular metabolism. This review highlights the important role of the interplay between mitochondrial and entire cell physiology, including signaling from and to mitochondria. Show less

In this work, three iridium(III) tetrazolato complexes have been designed and successfully synthesized. Beside photophysical properties, their performances in protein staining have been comprehensively investigated in this work for the first time. Notably, these iridium(III) tetrazolato complexes with high quantum efficiency exhibited much better protein staining properties than the commercial agent Coomassie Brilliant Blue (CBB) under the same experimental conditions, which may pave the way to explore new efficient iridium-based protein staining agents both for commercial markets and academic research in the future. Show less

We used all-atom Molecular Dynamics (MD) computer simulations to study the formation of pre-polymers between the four nucleotides in RNA (AMP, UMP, CMP, GMP) in the presence of different substrates that could have been present in a prebiotic environment. Pre-polymers are C3'-C5' hydrogen-bonded nucleotides that have been suggested to be the precursors of phosphodiester-bonded RNA polymers. We simulated wet-dry cycles by successively removing water molecules from the simulations, from ~60 to 3 water molecules per nucleotide. The nine substrates in this study include three clay minerals, one mica, one phosphate mineral, one silica, and two metal oxides. The substrates differ in their surface charge and ability to form hydrogen bonds with the nucleotides. From the MD simulations, we quantify the interactions between different nucleotides, and between nucleotides and substrates. For comparison, we included graphite as an inert substrate, which is not charged and cannot form hydrogen bonds. We also simulated the dehydration of a nucleotide-only system, which mimics the drying of small droplets. The number of hydrogen bonds between nucleotides and nucleotides and substrates was found to increase significantly when water molecules were removed from the systems. The largest number of C3'-C5' hydrogen bonds between nucleotides occurred in the graphite and nucleotide-only systems. While the surface of the substrates led to an organization and periodic arrangement of the nucleotides, none of the substrates was found to be a catalyst for pre-polymer formation, neither at full hydration, nor when dehydrated. While confinement and dehydration seem to be the main drivers for hydrogen bond formation, substrate interactions reduced the interactions between nucleotides in all cases. Our findings suggest that small supersaturated water droplets that could have been produced by geysers or springs on the primitive Earth may play an important role in non-enzymatic RNA polymerization. Show less

This study was intended to evaluate the anticancer activity of three newly synthesized iridium(III) complexes [Ir(ppy)₂(PEIP)](PF₆) (1) (ppy = 2-phenylpyridine, PEIP = 2-phenethyl-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy)₂(SIP)](PF₆) (2) (SIP = (E)-2-styryl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(ppy)₂(PEYIP)](PF₆) (3) (PEYIP = 2-phenethynyl-1H-imidazo[4,5-f][1,10]phenanthroline). The cytotoxic activity in vitro against A549, SGC-7901, HepG2, HeLa and normal NIH3T3 cells was investigated by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. We found that the complexes 1, 2 and 3 significantly inhibited cell proliferation, in particular, complexes 2 and 3 show high cytotoxic effect on SGC-7901 cells with an IC₅₀ value of 5.8 ± 0.7 and 4.4 ± 0.1 μM. Moreover, cell cycle assay revealed that the complexes could block G2/M phase of the cell cycle. Apoptotic evaluation by Annexin V/PI staining indicated that complexes 1-3 can induce apoptosis in SGC-7901 cells. In addition, microscopy detection suggested that disruption of mitochondrial functions, characterized by increased generation of intracellular ROS and Ca²⁺ as well as decrease of mitochondrial membrane potential. Western blot analysis shows that the complexes upregulate the expression of pro-apoptotic Bax and downregulate the expression of anti-apoptotic Bcl-2, which further activates caspase-3 and prompts the cleavage of PARP. Taken together, these results demonstrated that complexes 1-3 exert a potent anticancer effect on SGC-7901 cells via ROS-mediated endoplasmic reticulum stress-mitochondrial apoptotic pathway and have a potential to be developed as novel chemotherapeutic agents for human gastric cancer. Three new iridium(III) complexes [Ir(ppy)₂(PEIP)](PF₆) (1) (ppy = 2-phenylpyridine, PEIP = 2-phenethyl-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy)₂(SIP)](PF₆) (2) (SIP = 2-styryl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(ppy)₂(PEYIP)](PF₆) (3) (PEYIP = 2-phenethynyl-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized. The anticancer activity in vitro was investigated by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The results show that the complexes induce apoptosis via ROS-mediated endoplasmic reticulum stress-mitochondrial dysfunction pathway. Show less

Ruthenium complexes with good biological properties have attracted increasing attention in recent decades. In this work, three ruthenium polypyridine complexes containing 5-fluorouracil derivatives as ligands, [Ru(bpy)₂(L)]²⁺ (Ru1), [Ru(phen)₂(L)]²⁺ (Ru2), [Ru(dip)₂(L)]²⁺ (Ru3) (L = 1-((1,10-phenanthroline-5-amino) pentyl)-5-fluorouracil; bpy = 2,2'-bipyridine; phen =1,10-phenanthroline; dip = 4,7-diphenyl-1,10-phenanthroline), were synthesized and characterized. Based on in vitro cytotoxicity tests, Ru3 (IC₅₀ = 7.35 ± 0.39 μM) showed the best anticancer activity among three compounds in the selected cell lines. It is worth noting that Ru3 also exerts less cytotoxicity on LO2 cell lines, with an IC₅₀ value 5 times higher than that on HeLa cells, indicating its selective activity. Mechanism studies revealed that Ru3 can specifically target lysosomes and induce cell apoptosis in a caspase-dependent manner. Specifically, Ru3 can arrest cell cycle at the G0/G1 phase, increase the intracellular reactive oxygen species (ROS) level, and then damage DNA. In short, Ru3 can eventually cause cell death through the synergy of inducing apoptosis and autophagy, which was further proven by western blot assay results. Show less

Cancer is frequently caused by microRNAs, which control post-transcriptional levels of gene expression by binding to target mRNAs. MiR-29a-3p has recently been shown to play a twofold function in the majority of malignancies, including colorectal cancer (CRC), according to mounting evidence. Here, we not only briefly summarize such connection between miR-29a-3p and cancers, but aslo primarily evaluate the miR-29a-3p expression pattern, clinical applicability, and molecular mechanisms in CRC to provide a guide for future studies. This review established the diagnostic and prognostic value of miR-29a-3p abnormalty in a variety of clinical samples for CRC. Furthermore, current molecular mechanisms of miR-29a-3p for regulating cancerous biological processes such growth, invasion, metastasis, the epithelial-mesenchymal transformation process, and immunomodulation through its upstream regulatory factors and downstream targeted genes were briefly explored. More specifically, miR-29a-3p has been linked to a few medications that have been shown to have anticancer benefits. To sum up, miR-29a-3p is a promising biomarker and prospective therapeutic target for the diagnosis and prognosis of CRC, but further research is still needed to establish a theoretical basis for more practical applications. 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

One of the major goals of bioinorganic chemistry has been to mimic the function of elegant metalloenzymes. Such functional modeling has been difficult to attain in solution, in particular, for reactions that require multiple protons and multiple electrons (nH+/ne-). Using a combination of heterogeneous electrochemistry, electrode and molecule design one may control both electron transfer (ET) and proton transfer (PT) of these nH+/ne- reactions. Such control can allow functional modeling of hydrogenases (H+ + e- → 1/2 H2), cytochrome c oxidase (O2 + 4 e- + 4 H+ → 2 H2O), monooxygenases (RR'CH2 + O2 + 2 e- + 2 H+ → RR'CHOH + H2O) and dioxygenases (S + O2 → SO2; S = organic substrate) in aqueous medium and at room temperatures. In addition, these heterogeneous constructs allow probing unnatural bioinspired reactions and estimation of the inner- and outer-sphere reorganization energy of small molecules and proteins. Show less

Abstract The hallmark of tumorigenesis is the successful circumvention of cell death regulation for achieving unlimited replication and immortality. Ferroptosis is a newly identified type of cell death dependent on lipid peroxidation which differs from classical programmed cell death in terms of morphology, physiology and biochemistry. The broad spectrum of injury and tumor tolerance are the main reasons for radiotherapy and chemotherapy failure. The effective rate of tumor immunotherapy as a new treatment method is less than 30%. Ferroptosis can be seen in radiotherapy, chemotherapy, and tumor immunotherapy; therefore, ferroptosis activation may be a potential strategy to overcome the drug resistance mechanism of traditional cancer treatments. In this review, the characteristics and causes of cell death by lipid peroxidation in ferroptosis are briefly described. In addition, the three metabolic regulations of ferroptosis and its crosstalk with classical signaling pathways are summarized. Collectively, these findings suggest the vital role of ferroptosis in immunotherapy based on the interaction of ferroptosis with tumor immunotherapy, chemotherapy and radiotherapy, thus, indicating the remarkable potential of ferroptosis in cancer treatment. Show less

Subtle variations in the lipid composition of mitochondrial membranes can have a profound impact on mitochondrial function. The inner mitochondrial membrane contains the phospholipid cardiolipin, which has been demonstrated to act as a biomarker for a number of diverse pathologies. Small molecule dyes capable of selectively partitioning into cardiolipin membranes enable visualization and quantification of the cardiolipin content. Here we present a data-driven approach that combines a deep learning-enabled active learning workflow with coarse-grained molecular dynamics simulations and alchemical free energy calculations to discover small organic compounds able to selectively permeate cardiolipin-containing membranes. By employing transferable coarse-grained models we efficiently navigate the all-atom design space corresponding to small organic molecules with molecular weight less than ≈500 Da. After direct simulation of only 0.42% of our coarse-grained search space we identify molecules with considerably increased levels of cardiolipin selectivity compared to a widely used cardiolipin probe 10-N-nonyl acridine orange. Our accumulated simulation data enables us to derive interpretable design rules linking coarse-grained structure to cardiolipin selectivity. The findings are corroborated by fluorescence anisotropy measurements of two compounds conforming to our defined design rules. Our findings highlight the potential of coarse-grained representations and multiscale modelling for materials discovery and design. Show less

Ferroptosis is a form of programmed cell death characterized by intracellular iron accumulation and lipid peroxidation, and earlier studies identified glutathione peroxidase 4 (GPX4) as an essential regulator of this process. Ferroptosis plays an essential role in tumors, degenerative diseases, and ischemia-reperfusion injury. However, researchers have found that inhibition of GPX4 does not entirely suppress ferroptosis in certain diseases, or cells express resistance to ferroptosis agonists that inhibit GPX4. As research progresses, it has been discovered that there are multiple regulatory pathways for ferroptosis that are independent of GPX4. The study of GPX4-independent ferroptosis pathways can better target ferroptosis to prevent and treat various diseases. Here, the currently inhibited pulmonary GPX4-dependent ferroptosis pathways will be reviewed. Show less

Natural products represent an excellent source of unprecedented anticancer compounds. However, the identification of the mechanism of action remains a major challenge. Several techniques and methodologies have been considered, but with limited success. In this work, we explored the combination of live cell imaging and machine learning techniques as a promising tool to depict in a fast and affordable test the mode of action of natural compounds with antiproliferative activity. To develop the model, we selected the non-small cell lung cancer cell line SW1573, which was exposed to the known antimitotic drugs paclitaxel, colchicine and vinblastine. The novelty of our methodology focuses on two main features with the highest relevance, (a) meaningful phenotypic metrics, and (b) fast Fourier transform (FFT) of the time series of the phenotypic parameters into their corresponding amplitudes and phases. The resulting algorithm was able to cluster the microtubule disruptors, and meanwhile showed a negative correlation between paclitaxel and the other treatments. The FFT approach was able to group the samples as efficiently as checking by eye. This methodology could easily scale to group a large amount of data without visual supervision. Show less

Aerobic energy metabolism is driven by proton-pumping respiratory supercomplexes. The study reports the structural basis for energy conversion in such supercomplex. It may aid metabolic engineering and drug design against diphtheria and tuberculosis. Show less

TLDR: A small-molecule gold(III)-based agent bearing a chiral phosphine ligand that selectively disrupts mitochondrial metabolism in murine and human TNBC cells but not normal epithelial cells is described, highlighting the development of gold-based compounds targeting mitochondrial pathways for efficacious cancer treatment. Show less

Ru(II) polypyridyl complexes are widely used in biological fields, due to their physico-chemical and photophysical properties. In this paper, a series of new chiral Ru(II) polypyridyl complexes (1-5) with the general formula {Δ/Λ-[Ru(bpy)₂(X,Y-sal)]BF₄} (bpy = 2,2'-bipyridyl; X,Y-sal = 5-bromosalicylaldehyde (1), 3,5-dibromosalicylaldehyde (2), 5-chlorosalicylaldehyde (3), 3,5-dichlorosalicylaldehyde (4) and 3-bromo-5-chlorosalicylaldehy (5)) were synthesized and characterized by elemental analysis, FT-IR, and ¹H/¹³C NMR spectroscopy. Also, the structures of complexes 1 and 5 were determined by X-ray crystallography; these results showed that the central Ru atom adopts a distorted octahedral coordination sphere with two bpy and one halogen-substituted salicylaldehyde. DFT and TD-DFT calculations have been performed to explain the excited states of these complexes. The singlet states with higher oscillator strength are correlated with the absorption signals and are mainly described as ¹MLCT from the ruthenium centre to the bpy ligands. The lowest triplet states (T₁) are described as ³MLCT from the ruthenium center to the salicylaldehyde ligand. The theoretical results are in good agreement with the observed unstructured band at around 520 nm for complexes 2, 4 and 5. Biological studies on human cancer cells revealed that dihalogenated ligands endow the Ru(II) complexes with enhanced cytotoxicity compared to monohalogenated ligands. In addition, as far as the type of halogen is concerned, bromine is the halogen that provides the highest cytotoxicity to the synthesized complexes. All complexes induce cell cycle arrest in G0/G1 and apoptosis, but only complexes bearing Br are able to provoke an increase in intracellular ROS levels and mitochondrial dysfunction. Show less

AbstractNew mono- and di-nuclear thio-purine and thio-purine nucleoside gold(I) complexes were synthesized, characterized, and evaluated in vitro for biological activities in comparison to related known purine complexes. By combining known anti-tumoral thio-purines with R3PAu moieties as present in auranofin, complexes with enhanced effects and selectivities were obtained, which not only act as cytostatics, but also disrupt tumor-specific processes. Their IC50 values in cytotoxicity test with tumor cell lines ranged from three-digit nanomolar to single-digit micromolar, revealing a tentative structure–activity relationship (SAR). Both the residues R2 of the phosphane ligand and R1 at C2 of the pyrimidine ring had a significant impact on the cytotoxicity. In most cases, the introduction of a ribo-furanosyl group at N9 of the purine led to a distinctly more cytotoxic complex. Most complexes were more active against multi-drug-resistant tumor cells or such lacking functional p53 when compared to the respective untreated wild type cell lines. Some nucleoside complexes displayed an interesting dose-dependent dual mode of action regarding cell cycle arrest and DNA repair mechanism. Some phosphane(purine-6-thiolato)gold (I) complexes had a stronger inhibitory effect on the thioredoxin reductase (TrxR) and on the reactive oxygen species (ROS) generation in cancer cells than is typical of other gold complexes. They also led to DNA fragmentation and showed anti-angiogenic effects. Their stability under test conditions was demonstrated by 77Se NMR monitoring of an exemplary selenopurine complex. Graphical abstract Show less

Background

PT-112, the first pyrophosphate-platinum conjugate, causes immunogenic cell death in experimental models, leading to recruitment of tumour-infiltrating lymphocytes. PT-112 also associates with bone (osteotropism), likely driven by its pyrophosphate moiety. This is the first-in-human study of PT-112 monotherapy, exploring its safety and efficacy in a patient population where standard of care therapies were exhausted and novel treatment options are needed.

Methods

Patients with progressing, advanced solid tumours received PT-112 intravenously (1 h) on days 1, 8, 15 of a 28-day cycle in an open-label, multi-centre 3 + 3 dose-escalation trial, conducted at four US research sites. The primary objective was to assess safety and pharmacokinetics, and to identify a recommended phase 2 dose (RP2D). Eligibility criteria included: age ≥18 years, Eastern Collaborative Oncology Group (ECOG) Performance Status of 0-1, and disease evaluable by Response Evaluation Criteria in Solid Tumours (RECIST) v1·1 or by informative tumour markers. Patients receiving ≥1 dose of PT-112 were included in the safety and pharmacokinetic analyses, with the exploratory efficacy analysis including patients receiving ≥1 dose at 125 mg/m². This study is registered at ClinicalTrials.gov, number NCT02266745, with the dose-escalation portion of the study closed.

Findings

Between July 7th, 2014 and September 18th, 2018, 66 heavily pre-treated patients (median 4 prior lines, IQR 2-6) were enrolled and treated across 11 doses (12-420 mg/m²). Treatment-related adverse events included fatigue (23 patients, 35%), nausea (16 patients, 24%), and peripheral neuropathy (14 patients, 21%). Grade 3 events were experienced by 18 patients (27%), with no grade 4-5 events observed. The recommended phase 2 dose was determined to be 360 mg/m². Nine (17%) of the 54 efficacy evaluable patients achieved progression-free survival ≥6 months. Durable partial responses were induced in non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and thymoma. Radiographic and serum marker reductions were observed among ten patients with metastatic castration resistant prostate cancer, four of whom survived two years or longer.

Interpretation

PT-112 is safe and well-tolerated in a heavily pre-treated population. Prolonged responses were noted against thymoma and lung cancer, along with radiographic and serum marker improvement in prostate cancer. Given the heterogeneous patient population, subsequent studies will be needed to characterize the risk/benefit ratio in more homogenous settings. Further development of PT-112 is ongoing, as single-agent and in combination with immune checkpoint inhibition.

Funding

Funding was provided by Promontory Therapeutics Inc. Show less

We have synthesized a series of novel substituted sulfonyl ethylenediamine (en) Ru^II arene complexes 1-8 of [(η⁶-arene)Ru(R¹-SO₂-EnBz)X], where the arene is benzene, HO(CH₂)₂O-phenyl or biphenyl (biph), X = Cl or I, and R¹ is phenyl, 4-Me-phenyl, 4-NO₂-phenyl or dansyl. The 'piano-stool' structure of complex 3, [(η⁶-biph)Ru(4-Me-phenyl-SO₂-EnBz)I], was confirmed by X-ray crystallography. The values of their aqua adducts were determined to be high (9.1 to 9.7). Complexes 1-8 have antiproliferative activity against human A2780 ovarian, and A549 lung cancer cells with IC₅₀ values ranging from 4.1 to >50 μM, although, remarkably, complex 7 [(η⁶-biph)Ru(phenyl-SO₂-EnBz)Cl] was inactive towards A2780 cells, but as potent as the clinical drug cisplatin towards A549 cells. All these complexes also showed catalytic activity in transfer hydrogenation (TH) of NAD⁺ to NADH with sodium formate as hydride donor, with TOFs in the range of 2.5-9.7 h^-1. The complexes reacted rapidly with the thiols glutathione (GSH) and N-acetyl-L-cysteine (NAC), forming dinuclear bridged complexes [(η⁶-biph)₂Ru₂(GS)₃]^2- or [(η⁶-biph)₂Ru₂(NAC-H)₃]^2-, with the liberation of the diamine ligand which was detected by LC-MS. In addition, the switching on of fluorescence for complex 8 in aqueous solution confirmed release of the chelated DsEnBz ligand in reactions with these thiols. Reactions with GSH hampered the catalytic TH of NAD⁺ to NADH due to the decomposition of the complexes. Co-administration to cells of complex 2 [(η⁶-biph)Ru(4-Me-phenyl-SO₂-EnBz)Cl] with L-buthionine sulfoximine (L-BSO), an inhibitor of GSH synthesis, partially restored the anticancer activity towards A2780 ovarian cancer cells. Complex 2 caused a concentration-dependent G1 phase cell cycle arrest, and induced a significant level of reactive oxygen species (ROS) in A2780 human ovarian cancer cells. The amount of induced ROS decreased with increase in GSH concentration, perhaps due to the formation of the dinuclear Ru-SG complex. Show less