👤 Pan X

The photophysical and biological properties of two new phenanthroline-based ligand ruthenium complexes were investigated in detail. Their DNA interaction modes were determined to be the intercalation mode using spectra titration and viscosity measurements. Under irradiation, obvious photo-reduced DNA cleavages were observed in the two complexes via singlet oxygen generation. Furthermore, complex 2 showed higher DNA affinity, photocleavage activity, and singlet oxygen quantum yields than complex 1. The two complexes showed no toxicity towards tumor cells (HeLa, A549, and A375) in the dark. However, obvious photocytotoxicities were observed in the two complexes. Complex 2 exhibited large PIs (phototherapeutic indices) (ca. 400) towards HeLa cells. The study suggests that these complexes may act as DNA intercalators, DNA photocleavers, and photocytotoxic agents. Show less

The synthesis and the evaluation of the efficacy of a cycloruthenated complex, RuZ, is reported, to overcome multi-drug resistance (MDR) in cancer cells. RuZ can self-assemble into nanoaggregates in the cell culture medium, resulting in a high intracellular concentration of RuZ in MDR cancer cells. The self-assembly significantly decreases oxygen consumption and inhibits glycolysis, which decreases cellular adenosine triphosphate (ATP) levels. The decrease in ATP levels and its low affinity for the ABCB1 and ABCG2 transporters (which mediate MDR) significantly increase the retention of RuZ by MDR cancer cells. Furthermore, RuZ increases cellular oxidative stress, inducing DNA damage, and, in combination with the aforementioned effects of RuZ, increases the apoptosis of cancer cells. Proteomic profiling analysis suggests that the RuZ primarily decreases the expression of proteins that mediate glycolysis and aerobic mitochondrial respiration and increases the expression of proteins involved in apoptosis. RuZ inhibits the proliferation of 35 cancer cell lines, of which 7 cell lines are resistant to clinical drugs. It is also active in doxorubicin-resistant MDA-MB-231/Adr mouse tumor xenografts. To the best of our knowledge, the results are the first to show that self-assembled cycloruthenated complexes are efficacious in inhibiting the growth of MDR cancer cells. Show less

Ru(ii) complexes have attracted increasing attention as promising antitumor agents for their relatively low toxicity, high affinity to DNA molecules, and correlation with multiple targets. Meanwhile, quinolones are synthetic antibacterial agents widely used in the clinical practice. In this paper, two novel Ru(ii) complexes coordinated by levofloxacin (LOFLX), [Ru(bpy)₂(LOFLX)]·2ClO₄ (1), and [Ru(dmbpy)₂(LOFLX)]·2ClO₄ (2) (bpy = 2,2'-bipyridine, dmbpy = 4,4'-dimethyl-2,2'-bipyridine) were synthesized with high efficiency under microwave irradiation and characterized by ESI-MS, ¹H NMR, and ¹³C NMR. The binding behavior of these complexes with double-strand calf thymus DNA(CT-DNA) was investigated using spectroscopy, molecular docking, and density functional theory calculations. Results showed that 2 exhibited higher binding affinity than 1 and LOFLX. Further studies showed that 2 could induce the G2/M phase arrest of A549 cells via DNA damage. In summary, these results indicated that 2 could be developed as a potential anticancer agent in treatment of lung cancer through the induction of cell cycle arrest at G2/M phase by triggering DNA damage. Show less

Title: Cyclometalated Ru(II)-isoquinoline complexes overcome cisplatin resistance of A549/DDP cells by downregulation of Nrf2 via Akt/GSK-3β/Fyn pathway. Abstract: Both ruthenium (Ru) and isoquinoline (IQ) compounds are regarded as potential anticancer drug candidates. Here, we report the synthesis and characterization of three novel cyclometalated Ru(II)-isoquinoline complexes: RuIQ-3, RuIQ-4, and RuIQ-5, and evaluation of their in vitro cytotoxicities against a panel of cell lines including A549/DDP, a cisplatin-resistant human lung cancer cell line. A549/DDP 3D multicellular tumor spheroids (MCTSs) were also used to detect the drug resistance reversal effect of Ru(II)-IQ complexes. Our results indicated that the cytotoxic activities against cancer cells of Ru(II)-IQ complexes, especially RuIQ-5, were superior compared with cisplatin. In addition, RuIQ-5 exhibited low toxicity towards both normal HBE cells in vitro and zebrafish embryos in vivo. Further investigation on cellular mechanism of action indicated that after absorption by A549/DDP cells, RuIQ-5 was mainly distributed in the nucleus, which is different from cisplatin. Besides, RuIQ-5 could induce apoptosis through mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, ROS-mediated DNA damage, and cycle arrest at both S and G2/M phases. Moreover, RuIQ-5 could inhibit the overexpression of Nrf2 through regulation of Akt/GSK-3β/Fyn signaling pathway and hindering the nuclear translocation of Nrf2. Based on these findings, we firmly believe that the studied Ru(II)-IQ complexes hold great promise as anticancer therapeutics with high effectiveness and low toxicity. Show less

Near-infrared (NIR) emitters are important probes for biomedical applications. Nanoparticles (NPs) incorporating mono- and tetranuclear iridium(iii) complexes attached to a porphyrin core have been synthesized. They possess deep-red absorbance, long-wavelength excitation (635 nm) and NIR emission (720 nm). TD-DFT calculations demonstrate that the iridium-porphyrin conjugates herein combine the respective advantages of small organic molecules and transition metal complexes as photosensitizers (PSs): (i) the conjugates retain the long-wavelength excitation and NIR emission of porphyrin itself; (ii) the conjugates possess highly effective intersystem crossing (ISC) to obtain a considerably more long-lived triplet photoexcited state. These photoexcited states do not have the usual radiative behavior of phosphorescent Ir(iii) complexes, and they play a very important role in promoting the singlet oxygen (¹O₂) and heat generation required for photodynamic therapy (PDT) and photothermal therapy (PTT). The tetranuclear 4-Ir NPs exhibit high ¹O₂ generation ability, outstanding photothermal conversion efficiency (49.5%), good biocompatibility, low half-maximal inhibitory concentration (IC₅₀) (0.057 μM), excellent photothermal imaging and synergistic PDT and PTT under 635 nm laser irradiation. To our knowledge this is the first example of iridium-porphyrin conjugates as PSs for photothermal imaging-guided synergistic PDT and PTT treatment in vivo. Show less

Title: Photoactivated Osmium Arene Anticancer Complexes. Abstract: Half-sandwich Os-arene complexes exhibit promising anticancer activity, but their photochemistry has hardly been explored. To exploit the photocytotoxicity and photochemistry of Os-arenes, O,O-chelated complexes [Os(η6-p-cymene)(Curc)Cl] (OsCUR-1, Curc = curcumin) and [Os(η6-biphenyl)(Curc)Cl] (OsCUR-2), and N,N-chelated complexes [Os(η6-biphenyl)(dpq)I]PF6 (OsDPQ-2, dpq = pyrazino[2,3-f][1,10]phenanthroline) and [Os(η6-biphenyl)(bpy)I]PF6 (OsBPY-2, bpy = 2,2'-bipyridine), have been investigated. The Os-arene curcumin complexes showed remarkable photocytotoxicity toward a range of cancer cell lines (blue light IC50: 2.6-5.8 μM, photocytotoxicity index PI = 23-34), especially toward cisplatin-resistant cancer cells, but were nontoxic to normal cells. They localized mainly in mitochondria in the dark but translocated to the nucleus upon photoirradiation, generating DNA and mitochondrial damage, which might contribute toward overcoming cisplatin resistance. Mitochondrial damage, apoptosis, ROS generation, DNA damage, angiogenesis inhibition, and colony formation were observed when A549 lung cancer cells were treated with OsCUR-2. The photochemistry of these Os-arene complexes was investigated by a combination of NMR, HPLC-MS, high energy resolution fluorescence detected (HERFD), X-ray adsorption near edge structure (XANES) spectroscopy, total fluorescence yield (TFY) XANES spectra, and theoretical computation. Selective photodissociation of the arene ligand and oxidation of Os(II) to Os(III) occurred under blue light or UVA excitation. This new approach to the design of novel Os-arene complexes as phototherapeutic agents suggests that the novel curcumin complex OsCUR-2, in particular, is a potential candidate for further development as a photosensitizer for anticancer photoactivated chemotherapy (PACT). Show less

Amino acid transporters mediate substrates across cellular membranes and their fine-tuned regulations are critical to cellular metabolism, growth, and death. As the functional component of system Xc-, which imports extracellular cystine with intracellular glutamate release at a ratio of 1:1, SLC7A11 has diverse functional roles in regulating many pathophysiological processes such as cellular redox homeostasis, ferroptosis, and drug resistance in cancer. Notably, accumulated evidence demonstrated that SLC7A11 is overexpressed in many types of cancers and is associated with patients' poor prognosis. As a result, SLC7A11 becomes a new potential target for cancer therapy. In this review, we first briefly introduce the structure and function of SLC7A11, then discuss its pathological role in cancer. We next summarize current available data of how SLC7A11 is subjected to fine regulations at multiple levels. We further describe the potential inhibitors of the SLC7A11 and their roles in human cancer cells. Finally, we propose novel insights for future perspectives on the modulation of SLC7A11, as well as possible targeted strategies for SLC7A11-based anti-cancer therapies. Show less

With the rapidly growing biomedical literature, automatically indexing biomedical articles by Medical Subject Heading (MeSH), namely MeSH indexing, has become increasingly important for facilitating hypothesis generation and knowledge discovery. Over the past years, many large-scale MeSH indexing approaches have been proposed, such as Medical Text Indexer, MeSHLabeler, DeepMeSH and MeSHProbeNet. However, the performance of these methods is hampered by using limited information, i.e. only the title and abstract of biomedical articles. Show less

Inducing necroptosis in cancer cells is an effective approach to circumvent drug-resistance. Metal-based triggers have, however, rarely been reported. Ruthenium(II) complexes containing 1,1-(pyrazin-2-yl)pyreno[4,5-e][1,2,4]triazine were developed with a series of different ancillary ligands (Ru1-7). The combination of the main ligand with bipyridyl and phenylpyridyl ligands endows Ru7 with superior nucleus-targeting properties. As a rare dual catalytic inhibitor, Ru7 effectively inhibits the endogenous activities of topoisomerase (topo) I and II and kills cancer cells by necroptosis. The cell signaling pathway from topo inhibition to necroptosis was elucidated. Furthermore, Ru7 displays significant antitumor activity against drug-resistant cancer cells in vivo. To the best of our knowledge, Ru7 is the first Ru-based necroptosis-inducing chemotherapeutic agent. Show less

Combinational use of drugs has been a common strategy in cancer treatment because of synergistic advantages in reducing dose and toxicity, minimizing or delaying drug resistance. To improve the efficacy of chemotherapy, various potential combinations have been investigated. Ruthenium complex is considered a potential alternative of the platinum-based drugs due to its significant efficacy and safety. Previously, we reported that ruthenium(II) complex (Δ-Ru1) has great anticancer potential and minor toxicity toward normal tissues. However, the therapeutic efficacy and mechanism of action of ruthenium(II) complex combined with other anticancer drugs is still unknown. Here, we investigated the combinational effect of Δ-Ru1 and doxorubicin in different cancer cells. The data assessed by Chou-Talalay method showed significant synergism in MCF-7 cells. Furthermore, the results in antiproliferation efficacy indicated that the combination showed strong cytotoxicity and increasing apoptosis of MCF-7 cells in 2D and 3D multicellular tumor spheroids (MCTSs). Significant inhibition of MCF-7 cells accompanied with increased ROS generation was observed. Furthermore, the expression of PI3K/AKT was significantly down-regulated, while the expression of PTEN was strongly up-regulated in cells treated with combination of Δ-Ru1 and doxorubicin. The expression of NF-κB and XIAP decreased while the expression of P53 increased and associated with apoptosis. These findings suggest that the combination of ruthenium complex and doxorubicin has a significant synergistic effect by down-regulating the PI3K/AKT signaling pathway in MCF-7 cells. This study may trigger more research in ruthenium complex and combination therapy that will be able to provide opportunities for developing better therapeutics for cancer treatment. Show less

Polypyridyl ruthenium complexes as novel photosensitizers had drawn attention due to its high selectivity towards cancer cells and low toxicity to normal cells. Herein, we synthesized a lysosome-targeted polypyridyl ruthenium complex Rhein-Ru(bpy)₃ (bpy = 2,2'-bipyridine, rhein = 4,5-dihydroxy-9,10-dioxoanthracene-2-carboxylic acid), tethering with the Chinese medicine herb rhein. Rhein-Ru(bpy)₃ exhibited high phototoxicity with short time of irradiation against tumor cell lines with the IC₅₀ value of 2.4- 8.7 μM, and higher cytotoxicity against cisplatin-resistant A2780 cell lines, suggesting that Rhein-Ru(bpy)₃ could overcome the cisplatin resistance. Moreover, Rhein-Ru(bpy)₃ displayed low cytotoxicity towards cell lines in dark incubation, which was beneficial to reduce the toxic side effects towards normal cell lines. Besides, the confocal imaging and western blotting assay results suggested that Rhein-Ru(bpy)₃ could induce cancer cell death through the autophagy pathway. These results inspired us that lysosome-targeted photosensitizers based on ruthenium complexes showed great potential for photodynamic therapy (PDT) application in cancer treatment. Show less

Four triphenylamine/carbazole-modified half-sandwich ruthenium(ii) compounds [(η⁶-p-cymene)Ru(N/O^N)Cl]^0/+ with Schiff base chelating ligands (N/O^N) are synthesized and characterized. The introduction of Schiff base units effectively increases the antitumor activity of these compounds (IC₅₀: 1.70 ± 0.56-17.75 ± 3.10 μM), which, meanwhile, can inhibit the metastasis of tumor cells effectively. These compounds follow an energy-dependent cellular uptake mechanism, mainly accumulate in lysosomes to destroy their integrity, and then eventually promote apoptosis. In addition, these compounds can induce an increase of intracellular reactive oxygen species (ROS) levels and provide an antitumor mechanism of oxidation, which is confirmed by the decrease of mitochondrial membrane potential (MMP) and the catalytic oxidation of the coenzyme nicotinamide-adenine dinucleotide (NADH). All these indicate that these ruthenium(ii) compounds are expected to be dual-functional antitumor agents: anti-metastasis and lysosomal damage. Show less

Herein, we present a series of dual-targeted ruthenium-glucose conjugates that can function as two-photon absorption (TPA) PDT agents to effectively destroy tumors by preferentially targeting both tumor cells and mitochondria. The in vivo experiments revealed an excellent tumor inhibitory efficiency of the dual-targeted TPA PSs. Show less

Two new Ru(II) complexes containing O, O-chelated ligands, Ru(dip)₂(SA) (Ru-1) and Ru(dmp)₂(SA) (Ru-2) (dip = 4,7-diphenyl-1,10-phenanthroline; dmp = 2,9-dimethyl-1,10-phenanthroline; SA = salicylate) were synthesized to evaluate their cytotoxicity in vitro. These complexes were found to exhibit moderate antitumor activity to different types of human cancers, including A549 (human lung carcinoma), MCF-7 (breast cancer), HeLa (human cervical cancer), and HepG2 (human hepatocellular carcinoma) cell lines, but displayed low toxicity to human normal cell lines BEAS-2B (immortalized human bronchial epithelial cells) when compared with that of cisplatin. Further studies revealed that these complexes could induce apoptosis in A549 cells, including activating caspase family proteins and poly (ADP-ribose) polymerase (PARP), reducing Bcl-2/Bax and Bcl-xl/Bad ratio, enhancing cellular reactive oxygen species (ROS) accumulation, triggering DNA damage, decreasing mitochondrial membrane potential (MMP), and leading cytochrome c release from mitochondria. Notably, complex Ru-1 showed low toxicity to developing zebrafish embryos. The obtained results suggest that these new synthetic complexes have the potential to be developed as low-toxicity agents for lung cancer treatment. Show less

Photodynamic therapy (PDT) has been widely used in conjunction with molecular oxygen to cause cancer cell death. Hypoxia, the inherent property in solid tumors, is the obstacle during the process of PDT. It is urgent to develop PDT photosensitizers independent of the oxygen concentration. Herein, triphenylamine-modified Ru(ii) complexes have been used as photosensitizers to produce superoxide anions (O2-˙) and hydroxyl radicals (˙OH) through a type I photochemical process. Ru(ii) complexes with triphenylamine can provide a possibility to drive the reactive oxygen species production through low oxidation potential and good light-harvesting abilities. The investigation on light-mediated radical production showed that Ru4 could produce abundant ˙OH and O2-˙ compared to Ru1-Ru3 under hypoxic environments owing to the strong absorption. These radicals exhibit potent toxicity, which can damage the neighbouring biomolecules and cause the apoptosis of cancer cells. The PDT effect was evaluated in vitro under hypoxia, suggesting that Ru4 could maintain excellent performance in inducing a sharp decrease in the activity of cancer cells. Show less

Ru(II)-polypyridyl complexes are of increasing interest in photodynamic therapy (PDT) due to their easily tunable photophysical and photochemical properties. However, short-wavelength absorption of Ru(II)-polypyridyl complexes has limited their penetration depth in PDT. Herein, the series of Ru(II)-polypyridyl complexes 1-4 was designed by replacing one bipyridine in [Ru(bpy)₃]Cl₂ with Schiff bases (iminopyridine or iminoquinoline analogues) to achieve red-shifted absorption of Ru(II)-polypyridyl photosensitizers. To further shift the absorption to longer wavelength and improve the photobiological activity of Ru(II)-polypyridyl complexes, the three tris-heteroleptic Ru(II) complexes 5-7 with benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (dppn) as a ligand were designed to achieve long-lived intraligand (³IL) excited states. Cytotoxicity data against A549 and HepG2 cells revealed that complex 7 showed extraordinarily high cytotoxicity under 650 nm irradiation, resulting in IC₅₀ values of 56 and 63 nM with exceptionally large phototoxicity index (PI) values of 763 and 613, respectively. Thus, the resulting complex 7 with considerable red-light photocytotoxicity and high PI values shows a promising potential for therapeutic applications, which represents a new scaffold of Ru(II)-polypyridyl photosensitizers for PDT in the "therapeutic window". This study delivers a rational strategy for the design of tris-heteroleptic Ru(II) complexes as promising photosensitizers for cancer therapy. Show less

Herein a new series of organometallic half-sandwich Ru(Ⅱ) complexes bearing aryl-BIAN chelating ligands with various electron-withdrawing and electron-donating substituents have been developed as theranostic agents. All the complexes display much higher anti-proliferative potency than the clinical chemotherapeutic drug cisplatin towards seven cancer cell lines. The anti-proliferative efficacy of these complexes is correlated to their electron-withdrawing ability. Interestingly, complex Ru1 also potently suppresses cancer cell migration in vitro and effectively inhibit tumor growth in vivo in a CT26 colon cancer mouse xenograft model. Mechanisms of action studies display that Ru1 can favorably accumulate in lysosome and exerts anti-cancer potency by inducing a series of events related to lysosomal dysfunction in CT26 cells. Interestingly, inhibition of lysosomal enzymes leads to suppression of cytotoxicity and apoptosis induced by Ru1. Our results elucidate that complex Ru1 can elicit cytotoxicity through lysosome-mediated apoptosis in vitro and suppress tumor growth in vivo. Show less