ABSTRACT
Medicinal gold compounds, a novel class of potential anticancer drugs, are believed to produce their pharmacological effects mainly through direct gold binding to protein targets at the level of solvent exposed cysteine (or selenocysteine) residues. We have explored therein the reactions of a panel of seven representative gold compounds with the cysteine protease cathepsin B according to an established ESI MS approach. Detailed information on the mode of protein binding of these gold compounds is gained; notably, quite distinct patterns of cathepsin B metalation have emerged from these studies. It is shown that panel gold compounds interact preferentially, often exclusively, with the free cysteine located in the active site of the enzyme.
Subject(s)
Cathepsin B , Gold Compounds , Gold Compounds/chemistry , Gold Compounds/pharmacology , Cathepsin B/chemistry , Cysteine/chemistry , Spectrometry, Mass, Electrospray Ionization , Proteins/chemistryABSTRACT
Gold compounds form a new class of promising anticancer agents with innovative modes of action. It is generally believed that anticancer gold compounds, at variance with clinically established platinum drugs, preferentially target proteins rather than nucleic acids. The reactions of several gold compounds with a few model proteins have been systematically explored in recent years through ESI MS measurements to reveal adduct formation and identify the main features of those reactions. Here, we focus our attention on a group of five gold compounds of remarkable medicinal interest, i.e., Auranofin, Au(NHC)Cl, [Au(NHC)2]PF6, Aubipyc, and Auoxo6, and on their reactions with four different biomolecular targets, i.e., the proteins HEWL, hCA I, HSA and the C-terminal dodecapeptide of the enzyme thioredoxin reductase. Complete ESI MS data are available for those reactions due to previous experimental work conducted in our laboratory. From the comparative analysis of the ESI MS reaction profiles, some characteristic trends in the metallodrug-protein reactivity may be identified as detailed below. The main features are described and analyzed in this review. Overall, all these observations are broadly consistent with the concept that cytotoxic gold drugs preferentially target cancer cell proteins, with a remarkable selectivity for the cysteine and selenocysteine proteome. These interactions typically result in severe damage to cancer cell metabolism and profound alterations in the redox state, leading to eventual cancer cell death.
Subject(s)
Antineoplastic Agents , Gold Compounds , Gold Compounds/pharmacology , Gold/chemistry , Auranofin/pharmacology , Auranofin/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Thioredoxin-Disulfide ReductaseABSTRACT
Gold compounds have a long tradition in medicine and offer many opportunities for new therapeutic applications. Herein, we evaluated the lead compound Auranofin and five related gold(I) complexes as possible inhibitors of SARS-CoV-2 Main Protease (SARS-CoV-2 Mpro), a validated drug target for the COVID-19 disease. The investigational panel of gold compounds included Auranofin; three halido analogues, i.e., Au(PEt3)Cl, Au(PEt3)Br, and Au(PEt3)I; and two gold carbene complexes, i.e., Au(NHC)Cl and [Au(NHC)2]PF6. Notably, all these gold compounds, with the only exception of [Au(NHC)2]PF6, turned out to be potent inhibitors of the catalytic activity of SARS-CoV-2 Mpro: the measured Ki values were in the range 2.1-0.4 µM. The reactions of the various gold compounds with SARS-CoV-2 Mpro were subsequently investigated through electrospray ionization (ESI) mass spectrometry (MS) upon a careful optimization of the experimental conditions; the ESI MS spectra provided clear evidence for the formation of tight metallodrug-protein adducts and for the coordination of well defined gold-containing fragments to the SARS-CoV-2 Mpro, again with the only exception of [Au(NHC)2]PF6, The metal-protein stoichiometry was unambiguously determined for the resulting species. The crystal structures of the metallodrug- Mpro adducts were solved in the case of Au(PEt3)Br and Au(NHC)Cl. These crystal structures show that gold coordination occurs at the level of catalytic Cys 145 in the case of Au(NHC)Cl and at the level of both Cys 145 and Cys 156 for Au(PEt3)Br. Tight coordination of gold atoms to functionally relevant cysteine residues is believed to represent the true molecular basis of strong enzyme inhibition.
Subject(s)
Auranofin , COVID-19 Drug Treatment , Humans , Auranofin/pharmacology , Viral Proteins/chemistry , SARS-CoV-2 , Gold Compounds/pharmacology , Cysteine , Gold/pharmacologyABSTRACT
Brucellosis is an endemic zoonotic disease caused by Brucella species, which are intramacrophage pathogens that make treating this disease challenging. The negative effects of the treatment regime have prompted the development of new antimicrobials against brucellosis. A new treatment modality for antibiotic-resistant microorganisms is the use of nanoparticles (NPs). In this study, we examined the antibacterial activities of silver and gold NPs (SNPs and GNPs, respectively), the resistance developed by Brucella melitensis (B. melitensis) and Brucella abortus (B. abortus) strains and the toxicity of both of these NPs in experimental rats. To test the bactericidal effects of the SNPs and GNPs, we used 22 multidrug-resistant Brucella isolates (10 B. melitensis and 12 B. abortus). The minimal inhibitory concentrations (MICs) of both types of NPs were determined utilizing the microdilution technique. To test the stability of resistance, 7 B. melitensis and 6 B. abortus isolates were passaged ten times in culture with subinhibitory concentrations of NPs and another ten times without NPs. Histopathological analysis was completed after rats were given 0.25, 0.5, 1, and 2 mg/kg NPs orally for 28 consecutive days. The MIC values (µg/ml) of the 10-nm SNPs and 20-nm GNPs against B. melitensis were 22.43 ± 2.32 and 13.56 ± 1.22, while these values were 18.77 ± 1.33 and 12.45 ± 1.59 for B. abortus, respectively. After extensive in vitro exposure, most strains showed no resistance to the 10-nm SNPs or 20-nm GNPs. The NPs and antibiotics did not cross-react in any of the evolved Brucella strains. SNPs and GNPs at doses below 2 mg/kg were not harmful to rat tissue according to organ histopathological examinations. However, a greater dose of NPs (2 mg/kg) harmed all of the tissues studied. The bactericidal properties of NPs are demonstrated in this work. Brucella strains develop similar resistance to SNPs and GNPs, and at low dosages, neither SNPs nor GNPs were hazardous to rats.
Subject(s)
Anti-Bacterial Agents , Brucella , Brucellosis , Gold , Metal Nanoparticles , Silver , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/toxicity , Brucella/drug effects , Brucella abortus/drug effects , Brucella melitensis/drug effects , Brucellosis/drug therapy , Brucellosis/epidemiology , Gold/pharmacology , Gold/therapeutic use , Gold/toxicity , Gold Compounds/pharmacology , Gold Compounds/therapeutic use , Gold Compounds/toxicity , Metal Nanoparticles/therapeutic use , Metal Nanoparticles/toxicity , Rats , Silver/pharmacology , Silver/therapeutic use , Silver/toxicity , Silver Compounds/pharmacology , Silver Compounds/therapeutic use , Silver Compounds/toxicityABSTRACT
Integrating multifunctional nanostructures capable of radiotherapy and photothermal ablation is an emerging alternative in killing cancer cells. In this work, we report a novel plasmonic heterostructure formed by decorating AuPt nanoparticles (NPs) onto the surfaces of CuS nanosheets (AuPt@CuS NSs) as a highly effective nanotheranostic toward dual-modal photoacoustic/computed tomography imaging and enhanced synergistic radiophotothermal therapy. These heterostructures can confer higher photothermal conversion efficiency via the local electromagnetic enhancement as well as a greater radiation dose deposition in the form of glutathione depletion and reactive oxygen species generation. As a result, the depth of tissue penetration is improved, and hypoxia of the tumor microenvironment is alleviated. With synergistic enhancement in the efficacy of photothermal ablation and radiotherapy, the tumor can be eliminated without later recurrence. It is believed that these multifunctional heterostructures will play a vital role in future oncotherapy with the enhanced synergistic effects of radiotherapy and photothermal ablation under the guided imaging of a potential dual-modality system.
Subject(s)
Copper/pharmacology , Gold Compounds/pharmacology , Photothermal Therapy , Platinum Compounds/pharmacology , Radiopharmaceuticals/pharmacology , Animals , Cell Line, Tumor , Copper/chemistry , Female , Gold Compounds/chemistry , Mammary Neoplasms, Animal , Mice , Mice, Inbred BALB C , Neoplasms, Experimental , Platinum Compounds/chemistry , Radiopharmaceuticals/chemistry , Random AllocationABSTRACT
Exploring and developing a new type of nanoplatform with diagnosis and treatment to effectively cure tumors and reduce side effects has become a hot spot for researchers and is of great significance. Herein, a cancer theranostic nanoplatform with dual-imaging, dual-phototherapy and laser-responsiveness to tumor microenvironment was successfully assembled by liposome (Lip) co-loaded with oil-soluble Au4Cu4 nanoclusters (NCs) and water-soluble Au25 NCs via a simple film hydration method and subsequent extraction process. The prepared Au4Cu4/Au25@Lip nanoplatform with core-shell structure and about 50 nm of uniform sphere shape presented highly biocompatible, stability and passive targeting due to the enhanced permeability and retention (EPR) effect. Furthermore, the Lip composed of lecithin and cholesterol has good affinity with the cell membrane, which can realize the effective accumulation of photosensitizers at the tumor site, so that improving phototherapy effect and reducing the damage to normal tissue. The loaded oil-soluble Au4Cu4 NCs were firstly and pleasantly surprised to find possessed not only ideal photodynamic effect, but also preferable catalysis towards endogenous hydrogen peroxide (H2O2) decomposition to produce oxygen (O2) for improving the tumor hypoxic environment besides the excellent photoluminescence ability while the water-soluble Au25 NCs own outstanding photothermogenesis effect and also photoluminescence performance. The in vitro and in vivo experiment results proved that in the Au4Cu4/Au25@Lip nanoplatform, the performances of both NCs were complementary, which presenting considerable photothermal/fluorescence imaging (PTI/FI)-guided synergistic photothermal therapy (PTT)/O2-enhanced photodynamic therapy (PDT) effect for the tumor under the irradiation of near infrared (NIR) laser. This work provides a useful inspiration and paves a new way for the assembly of NCs or namomaterials with different properties into an integrated anti-tumor theranostic nanoplatform.
Subject(s)
Gold Compounds/pharmacology , Metal Nanoparticles/chemistry , Photosensitizing Agents/pharmacology , Theranostic Nanomedicine , Cell Survival/drug effects , Gold Compounds/chemistry , HeLa Cells , Humans , Oxygen , Photochemotherapy , Photosensitizing Agents/chemistry , Phototherapy , Reactive Oxygen Species , Tumor MicroenvironmentABSTRACT
Cisplatin and derivatives are highly effective in the treatment of a wide range of cancer types; however, these metallodrugs display low selectivity, leading to severe side effects. Additionally, their administration often results in the development of chemoresistance, which ultimately results in therapeutic failure. This scenario triggered the study of other transition metals with innovative pharmacological profiles as alternatives to platinum, ruthenium- (e.g., KP1339 and NAMI-A) and gold-based (e.g., Auranofin) complexes being among the most advanced in terms of clinical evaluation. Concerning the importance of improving the in vivo selectivity of metal complexes and the current relevance of ruthenium and gold metals, this review article aims to survey the main research efforts made in the past few years toward the design and biological evaluation of target-specific ruthenium and gold complexes. Herein, we give an overview of the inorganic and organometallic molecules conjugated to different biomolecules for targeting membrane proteins, namely cell adhesion molecules, G-protein coupled receptors, and growth factor receptors. Complexes that recognize the progesterone receptors or other targets involved in metabolic pathways such as glucose transporters are discussed as well. Finally, we describe some complexes aimed at recognizing cell organelles or compartments, mitochondria being the most explored. The few complexes addressing targeted gene therapy are also presented and discussed.
Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Gold Compounds/pharmacology , Ruthenium Compounds/pharmacology , Antineoplastic Agents/administration & dosage , Cell Adhesion Molecules/drug effects , Cell Line, Tumor , Coordination Complexes/administration & dosage , Gold Compounds/administration & dosage , Humans , Receptors, G-Protein-Coupled/drug effects , Receptors, Growth Factor/drug effects , Ruthenium Compounds/administration & dosageABSTRACT
The preparation of ointments from natural compounds is essential for accelerating infected wounds. This study investigated the effects of topical uses of gold nanoparticles (Au)/perlite (Au/Perl) nanocomposites (NCs) by the help of Urtica dioica extract and its chitosan-capped derivative (Chit) on methicillin-resistant Staphylococcus aureus (MRSA)-infected wound healing in a mouse model. Furthermore, Au/Perl/Chit nanocomposite was prepared using protonated chitosan solution. The physicochemical properties of the as-synthesized nanocomposites were also investigated. The effects of Au/Perl/Chit NC were assessed by antibacterial, histopathological parameters as well as molecular evaluations. Then, they were compared with synthetic agent of mupirocin. The results revealed that Au/Perl NC was mesoporous and spherical in a range of 13-15 nm. Topical administration of Au/Perl/Chit ointment accelerated wound healing by reducing bacteria colonization and wound rate enhancing collagen biosynthesis and re-epithelialization, the expressions of IL-10, PI3K, AKT, bFGF, and COL1A genes, which is in agreement with the obtained results for mupirocin. In conclusion, the results strongly demonstrated that administration of ointments prepared from Au/Perl and Au/Perl/Chit nanocomposites stimulates MRSA-infected wound healing by decreasing the length of healing time and regulating PI3K/AKT/bFGF signaling pathway and is a promising candidate in stimulating MRSA-infected wound regeneration.
Subject(s)
Aluminum Oxide/pharmacology , Anti-Bacterial Agents/pharmacology , Antioxidants/pharmacology , Chitosan/pharmacology , Gold Compounds/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Silicon Dioxide/pharmacology , Skin/drug effects , Staphylococcal Skin Infections/drug therapy , Urtica dioica/metabolism , Wound Healing/drug effects , Aluminum Oxide/metabolism , Animals , Anti-Bacterial Agents/metabolism , Antioxidants/metabolism , Cell Proliferation/drug effects , Chitosan/analogs & derivatives , Chitosan/metabolism , Disease Models, Animal , Drug Compounding , Fibroblasts/drug effects , Fibroblasts/metabolism , Fibroblasts/microbiology , Fibroblasts/pathology , Gold Compounds/metabolism , Green Chemistry Technology , Male , Methicillin-Resistant Staphylococcus aureus/pathogenicity , Mice , Mice, Inbred BALB C , NIH 3T3 Cells , Nanoparticles , Nanotechnology , Signal Transduction , Silicon Dioxide/metabolism , Skin/metabolism , Skin/microbiology , Skin/pathology , Staphylococcal Skin Infections/metabolism , Staphylococcal Skin Infections/microbiology , Staphylococcal Skin Infections/pathology , Time FactorsABSTRACT
BACKGROUND: Over the past few years, fabrication of nanoparticles (NPs) has been deployed widely in technologies and many concerns have emerged about the hazardous effect on human health after NPs exposure. OBJECTIVE: Green synthesis of gold NPs (AuNPs) and assessment of their activity in 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer mouse model. METHODS: Chloroauric acid (HAuCl4) was used in formation of AuNPs with the help of Curcuma longa as aqueous reducing extract and stabilizing agent at room temperature. Formed NPs were characterized with UV-Vis spectrometry, Fourier-transform infrared spectroscopy (FTIR), Zetasizer measurement, Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). Virgin female albino mice with DMBA-induced breast cancer were treated with formed AuNPs for 5 consecutive days and were dissected after 28 days of the beginning of treatment. RESULTS: UV-Vis spectrometry showed absorbance maximum peak at 530 nm for formed AuNPs, FTIR confirmed formation of plant extract layer around formed NPs; zetasizer measurement revealed 278.2 nm as an average size of produced NPs; SEM and TEM approved formation of monodisperse spherical AuNPs. Biochemical analysis of untreated breast cancer group revealed marked changes in liver and kidney functions manifested by raised activity levels of alanine transaminase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and creatinine. Whereas, the treated group with AuNPs post-breast cancer induction displayed reduction in the activities (of ALT, AST and creatinine), while the BUN activity level was raised. Histopathological examination showed heavy incidence of tumor foci in the breast and lymph nodes belonged to the untreated breast cancer group confirmed with intense response to Ki-67 antibodies. While the treated group with AuNPs post-breast cancer induction showed degenerated tumor foci in the breast and lymph nodes with weak response to Ki-67 antibodies. CONCLUSION: AuNPs were successfully synthesized using HAuCl4 and C. longa extract confirmed their ability to control DMBA-induced breast cancer in virgin female Swiss albino mice.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Chlorides/pharmacology , Gold Compounds/pharmacology , Green Chemistry Technology , Metal Nanoparticles , Nanomedicine , Neoplasms, Experimental/drug therapy , 9,10-Dimethyl-1,2-benzanthracene , Alanine Transaminase/blood , Animals , Antineoplastic Agents/chemistry , Aspartate Aminotransferases/blood , Blood Urea Nitrogen , Breast Neoplasms/blood , Breast Neoplasms/chemically induced , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Chlorides/chemistry , Creatinine/blood , Curcuma/chemistry , Excipients/chemistry , Female , Gold Compounds/chemistry , Mice , Neoplasms, Experimental/blood , Neoplasms, Experimental/chemically induced , Neoplasms, Experimental/pathology , Oxidation-Reduction , Plant Extracts/chemistry , Tumor Burden/drug effectsABSTRACT
Gold nanoparticle (AuNP)-based systems have been extensively investigated as diagnostic and therapeutic agents due to their tunable properties and easy surface functionalization. Upon cell uptake, AuNPs present an inherent cell impairment potential based on organelle and macromolecules damage, leading to cell death. Such cytotoxicity is concentration-dependent and completely undesirable, especially if unspecific. However, under non-cytotoxic concentrations, internalized AuNPs could potentially weaken cells and act as antitumor agents. Therefore, this study aimed to investigate the antitumor effect of ultrasmall AuNPs (~3 nm) stabilized by the anionic polysaccharide gum arabic (GA-AuNPs). Other than intrinsic cytotoxicity, the focus was downregulation of cancer hallmarks of aggressive tumors, using a highly metastatic model of melanoma. We first demonstrated that GA-AuNPs showed excellent stability under biological environment. Non-cytotoxic concentrations to seven different cell lines, including tumorigenic and non-tumorigenic cells, were determined by standard 2D in vitro assays. Gold concentrations ≤ 2.4 mg L-1 (16.5 nM AuNPs) were non-cytotoxic and therefore chosen for further analyses. Cells exposed to GA-AuNPs were uptaken by melanoma cells through endocytic processes. Next we described remarkable biological properties using non-cytotoxic concentrations of this nanomaterial. Invasion through an extracellular matrix barrier as well as 3D growth capacity (anchorage-independent colony formation and spheroids growth) were negatively affected by 2.4 mg L-1 GA-AuNPs. Additionally, exposed spheroids showed morphological changes, suggesting that GA-AuNPs could penetrate into the preformed tumor and affect its integrity. All together these results demonstrate that side effects, such as cytotoxicity, can be avoided by choosing the right concentration, nevertheless, preserving desirable effects such as modulation of key tumor cell malignancy features.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Movement/drug effects , Gold Compounds/pharmacology , Melanoma, Experimental/drug therapy , Metal Nanoparticles , Skin Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Stability , Endocytosis , Gold Compounds/chemistry , Gold Compounds/metabolism , Gold Compounds/toxicity , Gum Arabic/chemistry , Humans , Melanoma, Experimental/metabolism , Melanoma, Experimental/pathology , Metal Nanoparticles/chemistry , Metal Nanoparticles/toxicity , Mice , Nanomedicine , Neoplasm Invasiveness , Neoplasm Metastasis , Particle Size , Skin Neoplasms/metabolism , Skin Neoplasms/pathologyABSTRACT
The effect of gold nanoparticles (GNPs) synthesized in marine algae has been described in the context of skin, where they have shown potential benefit. Ecklonia stolonifera (ES) is a brown algae that belongs to the Laminariaceae family, and is widely used as a component of food and medicine due to its biological activities. However, the role of GNPs underlying cellular senescence in the protection of Ecklonia stolonifera gold nanoparticles (ES-GNPs) against UVA irradiation is less well known. Here, we investigate the antisenescence effect of ES-GNPs and the underlying mechanism in UVA-irradiated human dermal fibroblasts (HDFs). The DPPH and ABTS radical scavenging activity of ES extracts was analyzed. These analyses showed that ES extract has potent antioxidant properties. The facile and optimum synthesis of ES-GNPs was established using UV-vis spectra. The surface morphology and crystallinity of ES-GNPs were demonstrated using high resolution transmission electron microscopy (HR-TEM), energy dispersive spectroscopy (EDS), X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FT-IR). ES-GNPs presented excellent photocatalytic activity, as shown by the photo-degradation of methylene blue and rhodamine B. A cellular senescence model was established by irradiating HDFs with UVA. UVA-irradiated HDFs exhibited increased expression of senescence-associated ß-galactosidase (SA-ß-galactosidase). However, pretreatment with ES-GNPs resulted in reduced SA-ß-galactosidase activity in UVA-irradiated HDFs. Intracellular ROS levels and G1 arrest in UVA-irradiated HDFs were checked against the background of ES-GNP treatment to investigate the antisenescence effects of ES-GNPs. The results showed that ES-GNPs significantly inhibit UVA-induced ROS levels and G1 arrest. Importantly, ES-GNPs significantly downregulated the transcription and translation of MMP (matrix metalloproteinases)-1/-3, which regulate cellular senescence in UVA-irradiated HDFs. These findings indicate that our optimal ES-GNPs exerted an antisenescence effect on UVA-irradiated HDFs by inhibiting MMP-1/-3 expression. Collectively, we posit that ES-GNPs may potentially be used to treat photoaging of the skin.
Subject(s)
Cellular Senescence/drug effects , Fibroblasts/drug effects , Gold Compounds/pharmacology , Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase 3/metabolism , Metal Nanoparticles , Phaeophyceae/metabolism , Skin Aging/drug effects , Skin/drug effects , Cells, Cultured , Fibroblasts/enzymology , Fibroblasts/pathology , Fibroblasts/radiation effects , Gold Compounds/chemistry , Green Chemistry Technology , Humans , Matrix Metalloproteinase 1/genetics , Matrix Metalloproteinase 3/genetics , Oxidation-Reduction , Secondary Metabolism , Skin/enzymology , Skin/pathology , Skin/radiation effects , Ultraviolet RaysABSTRACT
The synthesis of a novel class of cyclometalated gold(III) complexes supported by benzoylpyridine, benzylpyridine, and (1R,2R)-(+)-1,2-diaminocyclohexane (DACH) ligands, along with their crystal structures, is reported. These compounds provide a new scaffold to investigate biological properties of gold(III) complexes. The six complexes were prepared and characterized, following reactions of (C,N) cyclometalated gold(III) scaffolds, [Au(C^N)Cl2] with DACH, which yielded a new series of cyclometaled gold(III), 3-5, of the type [Au(C^NH)(DACH)2]+ and the nitrogen-substituted cyclometalated Au(III), 6-8, of the type [Au(C^N)(DACH)]2+. Antiproliferative activity of these complexes in a panel of cancer cells showed promising results with IC50 in the micromolar range and selectivity over normal epithelial cells, MRC5. Whereas 8 shows minimal interaction with superhelical DNA except at high gold concentrations of 500 µM, complex 5 does not show interaction even at 1000 µM. The complexes display significant uptake in OVCAR8 cancer cells within 200-1200 pmol/million cells with the exception of complex 4. Differential cellular uptake was observed for the complexes; for example, while 3 and 8 display significant uptake, 4 showed minimal uptake. The compounds proved to be stable under physiological conditions and were minimally affected by either glutathione or sodium ascorbate. Cell cycle studies reveal a G1 arrest induced by representative complexes. The results reveal that enhanced Au(III) stabilization promoted by combined cyclometalated and DACH ligands may offer ligand tuning insights for novel anticancer drug design.
Subject(s)
Cyclohexylamines/chemistry , Cyclohexylamines/pharmacology , Gold Compounds/chemistry , Gold Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Ascorbic Acid/chemistry , Cell Line, Tumor , Computer Simulation , Crystallography, X-Ray , Glutathione/chemistry , Humans , Ligands , Models, Chemical , Models, Molecular , Molecular StructureABSTRACT
Using oral cancer cells ( in vitro) and in vivo xenograft mice model, we have systematically studied the detailed mechanism of anticancer activity of quinacrine-based hybrid silver (QAgNP) and gold (QAuNP) nanoparticles (NPs) and compared their efficacies. Both the NPs showed characteristic anti-cell proliferation profile in various cancer cells with minimally affecting the normal nontransformed breast epithelial MCF-10A cells. The IC50 values of QAuNP in various cancer cells were less compared to QAgNP and also found to be the lowest (0.5 µg/mL) in SCC-9 oral cancer cells. Although both NPs caused apoptosis by increased DNA damage, arresting at S phase and simultaneously inhibiting the DNA repair activity in cells, efficacy of QAuNP was better than that of QAgNP. NPs intercalated with DNA and inhibited the topoisomerase activity in cells. Alteration in expression of cell cycle regulatory (cyclins B1, E1, A2, etc.) and replication-related (MRE11, RPA, RFC, etc.) proteins were also observed after NP exposure to the cells. Accumulation of cells resulted in extended G/M phase after prolonged exposure of QAuNP in SCC-9 cells. Interestingly, depletion of geminin and increase of Cdt-1 along with CDC-6 suggest the formation of re-replication. Recovery of body weight and reduction in tumor volume were found in NP-treated xenograft mice. Induction of Bax/Bcl-xL, PARP-1 cleavage, p53, and p21 were noted in NP-treated xenograft mice tissue samples. Thus, data suggest that NP inhibits topoisomerase activity, thereby inhibiting DNA replication and inducing re-replication, which causes S-phase arrest, DNA damage, and finally apoptosis of the oral cancer cells. Also, it was found that anticancer activity of QAuNP is better than that of QAgNP.
Subject(s)
Antineoplastic Agents/therapeutic use , Chlorides/chemistry , Gold Compounds/chemistry , Head and Neck Neoplasms/drug therapy , Nanoparticles/chemistry , Quinacrine/chemistry , Silver Nitrate/chemistry , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Chlorides/pharmacology , DNA Damage/drug effects , Female , Gold Compounds/pharmacology , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , S Phase Cell Cycle Checkpoints/drug effects , Silver Nitrate/pharmacology , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Background Platinum-based anticancer drugs are widely used in the chemotherapy of human neoplasms. The major obstacle for the clinical use of this class of drugs is the development of resistance and toxicity. It is therefore very important to understand the chemical properties, transport and metabolic pathways and mechanism of actions of these compounds. There is a large body of evidence that therapeutic and toxic effects of platinum drugs on cells are not only a consequence of covalent adducts formation between platinum complexes and DNA but also with RNA and many proteins. These processes determine molecular mechanisms that underlie resistance to platinum drugs as well as their toxicity. Increased expression levels of various transporters and increased repair of platinum-DNA adducts are both considered as the most significant processes in the development of drug resistance. Functional genomics has an increasing role in predicting patients' responses to platinum drugs. Genetic polymorphisms affecting these processes may play an important role and constitute the basis for individualized approach to cancer therapy. Similar processes may also influence therapeutic potential of nonplatinum metal compounds with anticancer activity. Conclusions Cisplatin is the most frequently used platinum based chemotherapeutic agent that is clinically proven to combat different types of cancers and sarcomas.
Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Drug Resistance, Neoplasm/physiology , Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cisplatin/adverse effects , Cisplatin/chemistry , Cisplatin/pharmacokinetics , DNA Adducts/chemistry , DNA Repair , DNA, Neoplasm/drug effects , Drug Hypersensitivity/etiology , Drug Resistance, Neoplasm/genetics , Gold Compounds/pharmacology , Humans , Neoplasms/blood , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Palladium/pharmacology , Platinum Compounds/adverse effects , Platinum Compounds/pharmacokinetics , Platinum Compounds/pharmacology , Polymorphism, Genetic , Ruthenium/pharmacologyABSTRACT
PURPOSE: Interpenetrating network system (IPN), consisting of polyethylene glycol (PEG) -diacrylate (PEGdA) and modified gelatin, is a biocompatible and biodegradable hydrogel and has been studied for the local delivery of bioactive molecules and drugs. Gold(III) porphyrin(AuP) is a stable metal compound in the development for anticancer application when administered systemically. The aim of this work is to develop a novel formulation for AuP based on IPN for local delivery. METHODS: IPN loaded with AuP hydrogel was optimized and synthesized. Drug release kinetics, cytotoxicity against tumor cells, and antitumor activity in lung cancer bearing nude mice were studied. RESULTS: AuP released from the IPN followed a first order kinetics in vitro. The AuP loaded IPN showed higher cytotoxicity against human lung cancer cell lines compared to IPN only. In mice bearing human lung cancer xenograft, AuP loaded IPN inhibited tumor growth and reduced angiogenesis. No sign of systemic toxicity was observed for all treatment groups. CONCLUSION: AuP loaded IPN provides an improved formulation over systemic delivery for tumor inhibition to complement surgical intervention. Graphical Abstract Injectable multifunctional matrix of polyethylene glycol and gelatin derivatives for the delivery of gold porphyrinto inhibit tumor growth.
Subject(s)
Gold Compounds/pharmacology , Heterografts/drug effects , Hydrogels/pharmacology , Lung Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacology , Biocompatible Materials/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Gelatin/chemistry , Humans , Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry , Kinetics , Mice , Mice, Inbred BALB C , Mice, Nude , Neovascularization, Pathologic/drug therapy , Polyethylene Glycols/chemistry , Transplantation, Heterologous/methodsABSTRACT
This study was undertaken to establish the presence and the role of aquaporins (AQPs) in human platelets. Immunodetection with polyclonal antibodies and fluorescent microscopy suggest the presence of AQP isoforms - 0-7 and 9-12 - localized (in resting platelets) in the plasma membrane and in the dense and alpha granules. In thrombin- or monensin-treated platelets, the granules' AQPs become visible in the whole cell body, indicating the granules' swelling. In our studies on the role of AQPs in platelet responses we used tetrachloroauric acid (HAuCl4), a classical water channel blocker. We found that 10-100 µM of Au(III) inhibited the hypotonicity-, monensin (simulating the action of Na+/H+ exchanger)-, and collagen-evoked platelet swelling and reduced tritiated water uptake by platelets treated by collagen or monensin, indicating its ability to block water channels in these cells. HAuCl4, at the concentrations reducing water influx, did not induce cell lysis, alter the plasma membrane shape or the -SH group content. The inhibitor also failed to affect Na+ and Cl--related osmotic gradient formation and protein kinase D2 phosphorylation. In platelets activated by threshold concentrations of collagen, the thrombin receptor activating peptide, ADP, calcium ionophore A23187, phorbol ester and arachidonic acid, HAuCl4 (100 µM) completely inhibited secretion of ATP from dense granules but failed to reduce platelet aggregation. In collagen-stimulated platelets, HAuCl4 (10-100 µM) reduced secretion from dense and alpha granules, as well as lysosomes, in a dose-dependent manner. We conclude that human platelets possess numerous AQPs subtypes localized in the plasma and granule membranes. AQP-mediated water fluxes may be crucial for platelet volume regulation as well as secretion from dense and alpha granules and lysosomes.
Subject(s)
Aquaporins/metabolism , Blood Platelets/metabolism , Lysosomes/metabolism , Blood Platelets/drug effects , Chlorides/pharmacology , Collagen/metabolism , Cytoplasmic Granules/metabolism , Gold Compounds/pharmacology , Humans , Platelet Aggregation , Thrombin/pharmacologyABSTRACT
A series of cationic mixed cyclometallated (C^N)Au(iii) dithiocarbamate complexes has been synthesized in good yields [HC^N = 2-(p-t-butylphenyl)pyridine]. The crystal structure of [(C^N)AuS2CNEt2]PF6 (3) has been determined. The cytotoxic properties of the new complexes have been evaluated in vitro against a panel of human cancer cell lines and healthy cells and compared with a neutral mixed (C^C)Au(iii) dithiocarbamate complex (C^C = 4,4'-di-t-butylbiphenyl-2,2'-diyl). The complexes appeared to be susceptible to reduction by glutathione but were stable in the presence of N-acetyl cysteine. The potential mechanism of action of this class of compounds has been investigated by measuring the intracellular uptake of some selected complexes, by determining their interactions with higher order DNA structures, and by assessing the ability to inhibit thioredoxin reductase. The complexes proved unable to induce the formation of reactive oxygen species. The investigations add to the picture of the possible mode of action of this class of complexes.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Coordination Complexes/chemistry , Gold Compounds/pharmacology , Gold/chemistry , Thiocarbamates/pharmacology , Drug Screening Assays, Antitumor , Gold Compounds/chemistry , Humans , Tumor Cells, CulturedABSTRACT
Synthesis of gold nanoparticles (AuNPs) has become a needed domain of applied science. Biological method for synthesis of AuNPs by Trichoderma hamatum SU136 aqueous mycelial extract was achieved. The culture filtrate of the fungus was exposed to three different concentrations of gold chloride. The culture filtrate of the fungus was exposed to three different concentrations of gold chloride (0·25, 0·5 and 1·0 mmol l-1 ). In all cases, the gold ions (Au3+ ) were reduced to Au0 , leading to the formation of stable AuNPs. The AuNPs were identified by UV-visible spectrometry, TEM and FT-IR. The presence of a surface plasmon band around 530 nm indicates AuNPs synthesis. Trichoderma hamatum SU136 synthesized 5-30 nm sized; spherical, pentagonal and hexagonal morphologies of AuNPs by TEM. The existence and binding of proteins with nanoparticles was approved by FT-IR study. Parameters optimization showed the smallest size of AuNPs was obtained with (0·5 mmol l-1 gold chloride, pH 7 at 38°C). Interestingly, AuNPs exhibited antimicrobial activity against four pathogenic bacterial strains in the presence of the standard antibiotic, streptomycin. SIGNIFICANCE AND IMPACT OF THE STUDY: Mycosynthesis of AuNPs by Trichoderma hamatum would provide some useful data for oriented biosynthesis of AuNPs. In addition, the applications of mycosynthesized AuNPs were studied against some pathogenic bacteria. Therefore, the gained results detect that these antimicrobial nanoparticles could be explored as hopeful candidates for a variety of biomedical and pharmaceutical applications. This study should provide a further prudence for the fungal-mediated synthesis of AuNPs.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacillus subtilis/drug effects , Gold Compounds/pharmacology , Metal Nanoparticles/chemistry , Pseudomonas aeruginosa/drug effects , Serratia/drug effects , Staphylococcus aureus/drug effects , Trichoderma/metabolism , Anti-Bacterial Agents/chemistry , Bioreactors/microbiology , Drug Synergism , Gold/chemistry , Gold Compounds/chemistry , Spectroscopy, Fourier Transform Infrared , Streptomycin/pharmacology , Surface Plasmon ResonanceABSTRACT
Gold (Au0) and silver (Ag0) nanoparticles were synthesized using tannic acid (TA) as both reducing and stabilizer. Nanoparticles formation, stability, and interaction with TA were compared to citrate-coated nanoparticles and monitored by UV-Vis, zeta potential, and transmission electron microscopy. TA coating resulted in a red-shift and broadening of bands compared to citrate-coated nanoparticles (NPs-Cit). AgNPs-TA and AuNPs-TA are negatively charged with mean surface charge of -29.4 mV and -29.6 mV, respectively. TEM images showed polydispersety of AuNPs-TA (6-42 nm) and aggregation of AgNPs-TA (12-71 nm). In vitro assays of Leishmania amazonensis promastigotes showed an increment of antileishmanial activity for AgNPs-TA in relation to AgNPs-Cit, while AuNPs-TA and AuNPs-Cit did not affect the protozoas at tested concentrations. CC50 value for AgNPs-TA suggested that TA attenuates nanosilver toxicity comparatively to its precursor (Ag+). This investigation can contribute to the development of new, green, and fast produced drugs aiming at leishmaniasis treatment.
Subject(s)
Antiprotozoal Agents/pharmacology , Gold Compounds/pharmacology , Macrophages, Peritoneal/drug effects , Metal Nanoparticles/toxicity , Silver Compounds/pharmacology , Tannins/pharmacology , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/isolation & purification , Female , Gold Compounds/chemistry , Metal Nanoparticles/chemistry , Mice , Mice, Inbred BALB C , Microscopy, Electron, Transmission , Parasitic Sensitivity Tests , Silver Compounds/chemistry , Tannins/chemistry , Toxicity Tests/methodsABSTRACT
Since ancient times gold and its complexes have been used as therapeutics against different diseases. In modern medicine gold drugs have been applied for the treatment of rheumatoid arthritis, however, recently other medical applications have come into the focus of inorganic medicinal chemistry. This chapter provides a non-comprehensive overview of key developments in the field of gold anticancer drugs. Exciting findings on gold(I) and gold(III) complexes as antitumor agents are summarized together with a discussion of relevant aspects of their modes of action.