👤 He ML

Despite advances in understanding genetic susceptibility to cancer, much of cancer heritability remains unidentified. At the same time, the makeup of industrial chemicals in our environment only grows more complex. This gap in knowledge on cancer risk has prompted calls to expand cancer research to the comprehensive, discovery-based study of nongenetic environmental influences, conceptualized as the "exposome." Show less

The aim of the UniProt Knowledgebase (UniProtKB; https://www.uniprot.org/) is to provide users with a comprehensive, high-quality and freely accessible set of protein sequences annotated with functional information. In this publication, we describe ongoing changes to our production pipeline to limit the sequences available in UniProtKB to high-quality, non-redundant reference proteomes. We continue to manually curate the scientific literature to add the latest functional data and use machine learning techniques. We also encourage community curation to ensure key publications are not missed. We provide an update on the automatic annotation methods used by UniProtKB to predict information for unreviewed entries describing unstudied proteins. Finally, updates to the UniProt website are described, including a new tab linking protein to genomic information. In recognition of its value to the scientific community, the UniProt database has been awarded Global Core Biodata Resource status. Show less

Hepatic cancer is one of the main causes of cancer-related death worldwide. Cancer stem cells (CSCs) are a unique subset of cancer cells that promote tumour growth, maintenance, and therapeutic resistance, leading to recurrence. In the present work, the ability of a ruthenium complex containing 1,3-thiazolidine-2-thione (RCT), with the chemical formula [Ru(tzdt)(bipy)(dppb)]PF₆, to inhibit hepatic CSCs was explored in human hepatocellular carcinoma HepG2 cells. RCT exhibited potent cytotoxicity to solid and haematological cancer cell lines and reduced the clonogenic potential, CD133⁺ and CD44^high cell percentages and tumour spheroid growth of HepG2 cells. RCT also inhibited cell motility, as observed in the wound healing assay and transwell cell migration assay. RCT reduced the levels of Akt1, phospho-Akt (Ser473), phospho-Akt (Thr308), phospho-mTOR (Ser2448), and phospho-S6 (Ser235/Ser236) in HepG2 cells, indicating that interfering with Akt/mTOR signalling is a mechanism of action of RCT. The levels of active caspase-3 and cleaved PARP (Asp214) were increased in RCT-treated HepG2 cells, indicating the induction of apoptotic cell death. In addition, RCT modulated the autophagy markers LC3B and p62/SQSTM1 in HepG2 cells and increased mitophagy in a mt-Keima-transfected mouse embryonic fibroblast (MEF) cell model, and RCT-induced cytotoxicity was partially prevented by autophagy inhibitors. Furthermore, mutant Atg5^-/- MEFs and PentaKO HeLa cells (human cervical adenocarcinoma with five autophagy receptor knockouts) were less sensitive to RCT cytotoxicity than their parental cell lines, indicating that RCT induces autophagy-mediated cell death. Taken together, these data indicate that RCT is a novel potential anti-liver cancer drug with a suppressive effect on CSCs. Show less

In this work, we report on the synthesis and properties of a new sensitizer for photodynamic therapy applications, constituted by a ruthenium(ii) complex (1) featuring a ligand inspired from natural isoquinoline alkaloids. The spectroscopic analysis revealed that 1 is characterized by an intense red emission (λ _em = 620 nm, Φ = 0.17) when excited at 550 nm, a low energy radiation warranting for a safe therapeutic approach. The phototoxicity of 1 on human breast cancer (Hs578T) and melanoma (A375) cell lines was assessed after irradiation using a LED lamp (525 nm, total fluence 10 J cm^-2). In vitro biological assays indicated that the cytotoxicity of 1 was significantly enhanced by light reaching IC₅₀ values below the micromolar threshold. The cell damage induced by 1 proved to be strictly connected with the overproduction of reactive oxygen species (ROS) responsible for mitochondrial dysfunction leading to the activation of caspases and then to apoptosis, and for DNA photocleavage leading to cell cycle arrest. Show less

Cancer stem cells (CSCs) are defined as a rare population of cancer cells related to tumor initiation and maintenance. These cells are primarily responsible for tumor growth, invasion, metastasis, recurrence, and resistance to chemotherapy. In this paper, we demonstrated the ability of Ru(II)-based complexes containing 2-thiouracil derivatives with the chemical formulas trans-[Ru(2TU)(PPh₃)₂(bipy)]PF₆ (1) and trans-[Ru(6m2TU)(PPh₃)₂(bipy)]PF₆ (2) (where 2TU = 2-thiouracil and 6m2TU = 6-methyl-2-thiouracil) to suppress liver CSCs by targeting NF-κB and Akt/mTOR signaling. Complexes 1 and 2 displayed potent cytotoxic effects on cancer cell lines and suppressed liver CSCs from HepG2 cells. Increased phosphatidylserine exposure, loss of mitochondrial transmembrane potential, increased PARP (Asp214) cleavage, DNA fragmentation, chromatin condensation and cytoplasmic shrinkage were detected in HepG2 cells treated with these complexes. Mechanistically, complexes 1 and 2 target NF-κB and Akt/mTOR signaling in HepG2 cells. Cell motility inhibition was also detected in HepG2 cells treated with these complexes. Complexes 1 and 2 also inhibited tumor progression in mice with HepG2 cell xenografts and exhibited tolerable systemic toxicity. Taken together, these results indicate that these complexes are new anti-HCC drug candidates that can suppress liver CSCs. Show less

Ruthenium(II) polypyridyl complexes (RPCs) that emit from metal-to-ligand charge transfer (MLCT) states have been developed as DNA probes and are being examined as potential anticancer agents. Here, we report that MLCT-emissive RPCs that bind DNA undergo Förster resonance energy transfer (FRET) with Cy5.5-labeled DNA, forming mega-Stokes shift FRET pairs. Based on this discovery, we developed a simple and rapid FRET binding assay to examine DNA-binding interactions of RPCs with diverse photophysical properties, including non-"light switch" complexes [Ru(dppz)₂(5,5'dmb)]²⁺ and [Ru(PIP)₂(5,5'dmb)]²⁺ (dppz = dipyridophenazine, 5,5'dmb = 5,5'-dimethyl-2,2'-bipyridine, PIP = 2-phenyl-imidazo[4,5-f][1,10]phenanthroline). Binding affinities toward duplex, G-quadruplex, three-way junction, and mismatch DNA were determined, and derived FRET donor-acceptor proximities provide information on potential binding sites. Molecules characterized by this method demonstrate encouraging anticancer properties, including synergy with the PARP inhibitor Olaparib, and mechanistic studies indicate that [Ru(PIP)₂(5,5'dmb)]²⁺ acts to block DNA replication fork progression. Show less

Title: Exploring the in vitro anticancer activities of Re(I) picolinic acid and its fluorinated complex derivatives on lung cancer cells: a structural study. Abstract: Fifteen rhenium(I) tricarbonyl complexes of the form fac-[Re(N,O')(CO)3(X)], where N,O'-bidentate ligand = 2-picolinic acid (Pico); 3,5-difluoropyridine-2-carboxylic acid (Dfpc); 3-trifluoromethyl-pyridine-2-carboxylic acid (Tfpc) and X = H2O; pyrazole (Pz); pyridine (Py); imidazole (Im); and methanol (CH3OH) were synthesized using the '2 + 1' mixed ligand approach with an average yield of 84%. The complexes were characterized using the following spectroscopic techniques: IR, 1H and 13C NMR, UV/Vis, and single-crystal X-ray diffraction. The effect of the fluorine atoms on the backbone of the N,O'-bidentate ligand was investigated and a trend was noticed in the carbonyl stretching frequencies: with Pico < Tfpc < Dfpc. The in vitro biological screening on Vero (healthy mammalian), HeLa (cervical carcinoma) and A549 (lung cancer) cells revealed one toxic complex, fac-[Re(Pico)(CO)3(H2O)], with respective LC50 values of 9.0 ± 0.9, 15.8 ± 4.9 (SI = 0.570) and 20.9 ± 0.8 (SI = 0.430) μg/mL. As a result, it can be used as a positive control drug of toxicity. Show less

Two cationic ruthenium(II) 1,4,7-trithiacyclononane ([9]aneS₃) complexes of curcumin (curcH) and bisdemethoxycurcumin (bdcurcH), namely [Ru(curc)(dmso-S)([9]aneS₃)]Cl (1) and [Ru(bdcurc)(dmso-S)([9]aneS₃)]Cl (2) were prepared from the [RuCl₂(dmso-S)([9]-aneS₃)] precursor and structurally characterized, both in solution and in the solid state by X-ray crystallography. The corresponding PTA complexes [Ru(curc)(PTA)([9]aneS₃)]Cl (3) and [Ru(bdcurc)(PTA)([9]aneS₃)]Cl (4) have been also synthesized and characterized (PTA = 1,3,5-triaza-7-phosphaadamantane). Bioinorganic studies relying on mass spectrometry were performed on complexes 1-4 to assess their interactions with the model protein lysozyme. Overall, a rather limited reactivity with lysozyme was highlighted accompanied by a modest cytotoxic potency against three representative cancer cell lines. The moderate pharmacological activity is likely connected to the relatively high stability of these complexes. Show less

Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compounds formulated as [Ru(p-cymene)(L)Cl][CF₃SO₃] (L = 1,1-bis(methylenediphenylphosphano)ethylene, 1; L = 1,1-bis(diphenylphosphano)ethylene, 2), which were characterized by elemental analysis, mass spectrometry, ¹H and ³¹P{¹H} NMR, UV-vis and IR spectroscopy, conductivity measurements and cyclic voltammetry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cytotoxic activity was evaluated using the MTT assay against human tumor cells, namely ovarian (A2780) and breast (MCF7 and MDA-MB-231). Both complexes were active against breast adenocarcinoma cells, with complex 1 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC₅₀ values in the MCF7 cancer cells, complexes 1 and 2 presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of 1 and 2 in MCF7 cells might be associated with the induction of reactive oxygen species (ROS), leading to a combined cell death mechanism via apoptosis and autophagy. Despite the fact that in vitro a partial intercalation between complexes and DNA was observed, no MCF7 cell cycle delay or arrest was observed, indicating that DNA might not be a direct target. Complexes 1 and 2 both exhibited a moderate to strong interaction with human serum albumin, suggesting that protein targets may be involved in their mode of action. Their acute toxicity was evaluated in the zebrafish model. Complex 1 (the most toxic of the two) exhibited a lethal toxicity LC₅₀ value about 1 order of magnitude higher than any IC₅₀ concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy. Show less

Ninety-seven percent of drug-indication pairs that are tested in clinical trials in oncology never advance to receive U.S. Food and Drug Administration approval. While lack of efficacy and dose-limiting toxicities are the most common causes of trial failure, the reason(s) why so many new drugs encounter these problems is not well understood. Using CRISPR-Cas9 mutagenesis, we investigated a set of cancer drugs and drug targets in various stages of clinical testing. We show that-contrary to previous reports obtained predominantly with RNA interference and small-molecule inhibitors-the proteins ostensibly targeted by these drugs are nonessential for cancer cell proliferation. Moreover, the efficacy of each drug that we tested was unaffected by the loss of its putative target, indicating that these compounds kill cells via off-target effects. By applying a genetic target-deconvolution strategy, we found that the mischaracterized anticancer agent OTS964 is actually a potent inhibitor of the cyclin-dependent kinase CDK11 and that multiple cancer types are addicted to CDK11 expression. We suggest that stringent genetic validation of the mechanism of action of cancer drugs in the preclinical setting may decrease the number of therapies tested in human patients that fail to provide any clinical benefit. Show less

Organometallic Ru(II)-arene complexes have emerged as potential alternatives to platinum appended agents due to their wide range of interesting features such as stability in solution and solid, significant activity, less toxicity and hydrophobic property of arene moiety, etc. Hence, a series of Ru(II)-p-cymene complexes, [(η⁶-p-cymene)Ru(η²-N,N-L1)Cl]Cl (1), [(η⁶-p-cymene)Ru(η¹-N-L2)Cl₂] (2) and [(η⁶-p-cymene)Ru(η¹-N-L3)Cl₂] (3) were prepared from pyrazole based ligands [2-(1H-pyrazol-3-yl)pyridine (L1), 3-(furan-2-yl)-1H-pyrazole (L2) and 3-(thiophen-2-yl)-1H-pyrazole (L3)], and [RuCl₂-(η⁶-p-cymene)] dimer. The new Ru(II)-p-cymene complexes were well characterized by elemental analysis, and spectroscopic (FT-IR, UV-Visible, ¹H NMR, ¹³C NMR and mass) and crystallographic methods. The Ru(II)-p-cymene complexes (1-3) were found to adopt their characteristic piano stool geometry around Ru(II) ion. The calf thymus DNA (CT-DNA) binding ability of the new complexes was investigated by electronic absorption spectroscopic titration and viscosity methods. The molecular docking study results showed that complex 1 strongly bound with targeted biomolecules than 2 and 3. Docked poses of bidentate pyrazole based Ru(II)-p-cymene complex 1 revealed that the complex formed a crucial guanine N⁷ position hydrogen bond with DNA receptor. Complexes 1-3 might hydrolyze under physiological conditions and form aqua complexes 4-8, and docking calculations showed that the aqua complexes bound strongly with the receptors than original complexes. The in vitro cytotoxicity of the Ru(II)-p-cymene complexes and cisplatin was evaluated against triple negative breast cancer (TNBC) MDA-MB-231 cells. Our results showed that the inhibitory effect of bidentate pyrazole based Ru(II)-p-cymene complex 1 on the growth of breast cancer cells was superior to other tested complexes. Show less

Two novel series of (salen)ruthenium(iii) complexes bearing guanidine and amidine axial ligands were synthesized, characterized, and evaluated for anticancer activity. In vitro cytotoxicity tests demonstrate that these complexes are cytotoxic against various cancer cell lines and the leading complexes have remarkable cancer-cell selectivity. A detailed study of the guanidine complex 7 and the amidine complex 13 reveals two distinguished modes of action. Complex 7 weakly binds to DNA and induces DNA damage, cell cycle arrest, and typical apoptosis pathways in MCF-7 cells. In contrast, complex 13 induces paraptosis-like cell death hallmarked by massive vacuole formation, mitochondrial swelling, and ER stress, resulting in significant cytotoxicity against human breast cancer cells. Our results provide an extraordinary example of tuning the mechanism of action of (salen)ruthenium(iii) anticancer complexes by modifying the structure of the axial ligands. Show less

The limitations of platinum complexes in cancer treatment have motivated the extensive investigation into other metal complexes such as ruthenium. We herein present the synthesis and characterization of a new family of ruthenium compounds 1a-5a with the general formula [Ru(bipy)₂L][CF₃SO₃]₂ (bipy = 2,2'-bipyridine; L = bidentate ligand: N,N; N,P; P,P; P,As) which have been characterized by elemental analysis, ES-MS, ¹H and ³¹P-{¹H} NMR, FTIR and conductivity measurements. The molecular structures of four Ru(ii) complexes were determined by single crystal X-ray diffraction. All compounds displayed moderate cytotoxic activity in vitro against human A2780 ovarian, MCF7 breast and HCT116 colorectal tumor cells. Compound 5a was the most cytotoxic compound against A2780 and MCF7 tumor cells with an IC₅₀ of 4.75 ± 2.82 μM and 20.02 ± 1.46 μM, respectively. The compounds showed no cytotoxic effect on normal human primary fibroblasts but rather considerable selectivity for A2780, MCF7 and HCT116 tumor cells. All compounds induce apoptosis and autophagy in A2780 ovarian carcinoma cells and some nuclear DNA fragmentation. All compounds interact with CT-DNA with intrinsic binding constants in the order 1a > 4a > 2a > 3a > 5a. The observed hyperchromic effect may be due to the electrostatic interaction between positively charged cations and the negatively charged phosphate backbone at the periphery of the double helix-CT-DNA. Interestingly, compound 1a shows a concentration dependent DNA double strand cleavage. In addition in vivo toxicity has been evaluated on zebrafish embryos unveiling the differential toxicity between the compounds, with LC₅₀ ranging from 8.67 mg L^-1 for compound 1a to 170.30 mg L^-1 for compound 2a. Show less

Described is a novel organorhodium(I) complex that is cytotoxic to the colon cancer cell line HCT116 and alters cell migration, DNA replication, and DNA condensation. Most importantly, the mechanism observed is not seen for the parent organorhodium dimer complex [{RhCl(COD)}2], RhCl3, or the free ligand/proligands (COD and 1-(n)butyl-3-methylimidazolium chloride). Thus, the activity of this organorhodium complex is attributable to its unique structure. Show less

Cationic ruthenium(II) pentamethylcyclopentadienyl benzenesulfonamide sandwich complexes have been synthesized and screened for enzymatic inhibition of the physiologically dominant carbonic anhydrase (CA) isozymes: human CA I and II, mitochondrial isozymes VA and VB, and the cancer-associated isozyme IX. The complexes demonstrated weaker binding to CAs compared with typical aromatic sulfonamides, inhibiting the enzyme at high nanomolar concentrations. An in vitro cytotoxic evaluation of the complexes was also undertaken against a range of tumorigenic cell lines and a healthy human cell line. Complexes inhibited the growth of cancerous cells at low micromolar concentrations while expressing lower levels of toxicity towards the normal human cell line. Factors influencing the synthesis, cytotoxicity, and enzyme affinity for this series of organometallic complexes are discussed. Show less

The synthesis and in vitro anticancer activity of dihalogenido(eta6-p-cymene)(3,5,6-bicyclophosphite-alpha-D-glucofuranoside)ruthenium(II) complexes are described. The compounds were characterized by NMR spectroscopy and ESI mass spectrometry, and the molecular structures of dichlorido-, dibromido- and diiodido(eta6-p-cymene)(3,5,6-bicyclophosphite-1,2-O-isopropylidene-alpha-D-glucofuranoside)ruthenium(II) were determined by X-ray diffraction analysis. The complexes were shown to undergo aquation of the first halido ligand in aqueous solution, followed by hydrolysis of a P--O bond of the phosphite ligand, and finally formation of dinuclear species. The hydrolysis mechanism was confirmed by DFT calculations. The aquation of the complexes was markedly suppressed in 100 mM NaCl solution, and notably only very slow hydrolysis of the P--O bond was observed. The complexes showed affinity towards albumin and transferrin and monoadduct formation with 9-ethylguanine. In vitro studies revealed that the 3,5,6-bicyclophosphite-1,2-O-cyclohexylidene-alpha-D-glucofuranoside complex is the most cytotoxic compound in human cancer cell lines (IC50 values from 30 to 300 microM depending on the cell line). Show less