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Biochemical and Biophysical Research... Dec 2022Osteoarthritis, a prevalent orthopedic disease, can affect the elderly and causes impairment. The degradation and aberrant homeostasis of cartilage extracellular matrix...
Osteoarthritis, a prevalent orthopedic disease, can affect the elderly and causes impairment. The degradation and aberrant homeostasis of cartilage extracellular matrix figure pivotally in the progression of osteoarthritis. Thioredoxin systems plays a role in a wide range of biological processes, including cell proliferation, apoptosis, and oxidative stress. The present study aimed to investigate the unique function and underlying pathophysiological mechanism of TXNRD1 in chondrocytes. An upregulated expression of TXNRD1 was observed in the articular cartilage of osteoarthritis patients compared with normal articular cartilage. Furthermore, in vitro experiments showed that the expression of TXNRD1 was also abnormally increased in IL-1β-induced primary mouse chondrocytes. Silencing TXNRD1 using siRNA in chondrocytes could effectively inhibit the expression of ADAMTS5 and MMP13, and enhance the expression of COL2A1 and SOX9. The same was true for auranofin, an inhibitor of TXNRD1. This phenomenon indicated that inhibition of TXNRD1 attenuated il-1β-induced metabolic imbalance of extracellular matrix (ECM) and the progression of chondrocyte osteoarthritis. Further mechanism analysis revealed that the activation of Nrf2 signaling pathway and the expression of heme oxygenase-1 (HO-1) were increased upon TXNRD1 inhibition. Furthermore, auranofin was found to attenuate DMM-induced osteoarthritis progression in vivo. Therefore, the pharmacological downregulation of TXNRD1 may provide an effective novel therapy for OA.
Topics: Animals; Mice; Auranofin; Cartilage, Articular; Chondrocytes; Extracellular Matrix; Interleukin-1beta; NF-E2-Related Factor 2; Osteoarthritis; Thioredoxin Reductase 1
PubMed: 36308906
DOI: 10.1016/j.bbrc.2022.10.059 -
Journal of Toxicology and Environmental... Jan 2021Auranofin is a gold complex used as an anti-rheumatic agent and may act as a potent anticancer drug against breast tumors. Trametinib is a specific mitogen-activated...
Auranofin is a gold complex used as an anti-rheumatic agent and may act as a potent anticancer drug against breast tumors. Trametinib is a specific mitogen-activated protein kinase inhibitor, approved for the treatment of metastatic melanoma. The aim of this study was to examine the synergistic effects of auranofin and trametinib on apoptosis in MCF-7 human breast cancer cells. The combination treatment inhibited cancer cell proliferation and induced cell cycle arrest at the sub-G1 phase and apoptosis via poly (ADP-ribose) polymerase cleavage and caspase-3/7 activation. It is noteworthy that this treatment significantly increased p38 mitogen-activated protein kinase (MAPK) phosphorylation to induce mitochondrial stress, subsequently promoting cancer cell apoptosis through release of apoptosis-inducing factor. Further data demonstrated that combined treatment significantly induced increase in nuclear translocation of AIF. These results indicated that activation of the p38 MAPK signaling pathway and mitochondrial apoptosis may contribute to the synergistic consequences in MCF-7 cells. Collectively, our data demonstrated that combined treatment with auranofin and trametinib exhibited synergistic breast cancer cell death and this combination might be utilized as a novel therapeutic strategy for breast cancer.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Auranofin; Breast Neoplasms; Cell Proliferation; Female; Humans; MCF-7 Cells; Pyridones; Pyrimidinones; p38 Mitogen-Activated Protein Kinases
PubMed: 33103613
DOI: 10.1080/15287394.2020.1835762 -
Archives of Pharmacal Research Mar 2023Drug repositioning has gained significant attention over the past several years. The anti-rheumatoid arthritis drug auranofin has been investigated for the treatment of...
Drug repositioning has gained significant attention over the past several years. The anti-rheumatoid arthritis drug auranofin has been investigated for the treatment of other diseases, including liver fibrosis. Because auranofin is rapidly metabolized, it is necessary to identify the active metabolites of auranofin that have detectable levels in the blood and reflect its therapeutic effects. In the present study, we investigated whether aurocyanide as an active metabolite of auranofin, can be used to evaluate the anti-fibrotic effects of auranofin. Incubation of auranofin with liver microsomes showed that auranofin was susceptible to hepatic metabolism. Previously, we found that the anti-fibrotic effects of auranofin are mediated via system x-dependent inhibition of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Therefore, we tried to identify active metabolites of auranofin based on their inhibitory effects on system x and NLRP3 inflammasome in bone marrow-derived macrophages. Among the seven candidate metabolites, 1-thio-β-D-glycopyrano-sato-S-(triethyl-phosphine)-gold(I) and aurocyanide potently inhibited system x and NLRP3 inflammasome. A pharmacokinetics study on mice detected significant plasma levels of aurocyanide after auranofin administration. Oral administration of aurocyanide significantly prevented thioacetamide-induced liver fibrosis in mice. Moreover, the in vitro anti-fibrotic effects of aurocyanide were assessed in LX-2 cells, where aurocyanide significantly decreased the migratory ability of the cells. In conclusion, aurocyanide is metabolically stable and detectable in plasma, and has inhibitory effects on liver fibrosis, suggesting that it is a potential marker of the therapeutic effects of auranofin.
Topics: Mice; Animals; Auranofin; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Mice, Inbred NOD; Gold; Liver Cirrhosis
PubMed: 36894745
DOI: 10.1007/s12272-023-01438-1 -
ACS Nano Mar 2024Ferroptotic cancer therapy has been extensively investigated since the genesis of the ferroptosis concept. However, the therapeutic efficacy of ferroptosis induction in...
Ferroptotic cancer therapy has been extensively investigated since the genesis of the ferroptosis concept. However, the therapeutic efficacy of ferroptosis induction in heterogeneous and plastic melanoma has been compromised, because the melanocytic and transitory cell subpopulation is resistant to iron-dependent oxidative stress. Here, we report a phenotype-altering liposomal nanomedicine to enable the ferroptosis-resistant subtypes of melanoma cells vulnerable to lipid peroxidation via senescence induction. The strategy involves the ratiometric coencapsulation of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (palbociclib) and a ferroptosis inducer (auranofin) within cRGD peptide-modified targeted liposomes. The two drugs showed a synergistic anticancer effect in the model B16F10 melanoma cells, as evidenced by the combination index analysis (<1). The liposomes could efficiently deliver both drugs into B16F10 cells in a targeted manner. Afterward, the liposomes potently induced the intracellular redox imbalance and lipid peroxidation. Palbociclib significantly provoked cell cycle arrest at the G/G phase, which sensitized auranofin-caused ferroptosis through senescence induction. Meanwhile, palbociclib depleted intracellular glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), further boosting ferroptosis. The proof-of-concept was also demonstrated in the B16F10 tumor-bearing mice model. The current work offers a promising ferroptosis-targeting strategy for effectively treating heterogeneous melanoma by manipulating the cellular plasticity.
Topics: Animals; Mice; Melanoma; Liposomes; Ferroptosis; Coenzymes; Auranofin; Lipid Peroxidation
PubMed: 38390865
DOI: 10.1021/acsnano.3c10142 -
Journal of Experimental & Clinical... Mar 2024This study explores the repurposing of Auranofin (AF), an anti-rheumatic drug, for treating non-small cell lung cancer (NSCLC) adenocarcinoma and pancreatic ductal...
Auranofin repurposing for lung and pancreatic cancer: low CA12 expression as a marker of sensitivity in patient-derived organoids, with potentiated efficacy by AKT inhibition.
BACKGROUND
This study explores the repurposing of Auranofin (AF), an anti-rheumatic drug, for treating non-small cell lung cancer (NSCLC) adenocarcinoma and pancreatic ductal adenocarcinoma (PDAC). Drug repurposing in oncology offers a cost-effective and time-efficient approach to developing new cancer therapies. Our research focuses on evaluating AF's selective cytotoxicity against cancer cells, identifying RNAseq-based biomarkers to predict AF response, and finding the most effective co-therapeutic agents for combination with AF.
METHODS
Our investigation employed a comprehensive drug screening of AF in combination with eleven anticancer agents in cancerous PDAC and NSCLC patient-derived organoids (n = 7), and non-cancerous pulmonary organoids (n = 2). Additionally, we conducted RNA sequencing to identify potential biomarkers for AF sensitivity and experimented with various drug combinations to optimize AF's therapeutic efficacy.
RESULTS
The results revealed that AF demonstrates a preferential cytotoxic effect on NSCLC and PDAC cancer cells at clinically relevant concentrations below 1 µM, sparing normal epithelial cells. We identified Carbonic Anhydrase 12 (CA12) as a significant RNAseq-based biomarker, closely associated with the NF-κB survival signaling pathway, which is crucial in cancer cell response to oxidative stress. Our findings suggest that cancer cells with low CA12 expression are more susceptible to AF treatment. Furthermore, the combination of AF with the AKT inhibitor MK2206 was found to be particularly effective, exhibiting potent and selective cytotoxic synergy, especially in tumor organoid models classified as intermediate responders to AF, without adverse effects on healthy organoids.
CONCLUSION
Our research offers valuable insights into the use of AF for treating NSCLC and PDAC. It highlights AF's cancer cell selectivity, establishes CA12 as a predictive biomarker for AF sensitivity, and underscores the enhanced efficacy of AF when combined with MK2206 and other therapeutics. These findings pave the way for further exploration of AF in cancer treatment, particularly in identifying patient populations most likely to benefit from its use and in optimizing combination therapies for improved patient outcomes.
Topics: Humans; Auranofin; Carcinoma, Non-Small-Cell Lung; Proto-Oncogene Proteins c-akt; Lung Neoplasms; Drug Repositioning; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Adenocarcinoma; Antineoplastic Agents; Lung; Biomarkers; Organoids; Carbonic Anhydrases
PubMed: 38515178
DOI: 10.1186/s13046-024-03012-z -
Cells Oct 2021Targeting the redox balance of malignant cells via the delivery of high oxidative stress unlocks a potential therapeutic strategy against glioblastoma (GBM). We...
Targeting the redox balance of malignant cells via the delivery of high oxidative stress unlocks a potential therapeutic strategy against glioblastoma (GBM). We investigated a novel reactive oxygen species (ROS)-inducing combination treatment strategy, by increasing exogenous ROS via cold atmospheric plasma and inhibiting the endogenous protective antioxidant system via auranofin (AF), a thioredoxin reductase 1 (TrxR) inhibitor. The sequential combination treatment of AF and cold atmospheric plasma-treated PBS (pPBS), or AF and direct plasma application, resulted in a synergistic response in 2D and 3D GBM cell cultures, respectively. Differences in the baseline protein levels related to the antioxidant systems explained the cell-line-dependent sensitivity towards the combination treatment. The highest decrease of TrxR activity and GSH levels was observed after combination treatment of AF and pPBS when compared to AF and pPBS monotherapies. This combination also led to the highest accumulation of intracellular ROS. We confirmed a ROS-mediated response to the combination of AF and pPBS, which was able to induce distinct cell death mechanisms. On the one hand, an increase in caspase-3/7 activity, with an increase in the proportion of annexin V positive cells, indicates the induction of apoptosis in the GBM cells. On the other hand, lipid peroxidation and inhibition of cell death through an iron chelator suggest the involvement of ferroptosis in the GBM cell lines. Both cell death mechanisms induced by the combination of AF and pPBS resulted in a significant increase in danger signals (ecto-calreticulin, ATP and HMGB1) and dendritic cell maturation, indicating a potential increase in immunogenicity, although the phagocytotic capacity of dendritic cells was inhibited by AF. In vivo, sequential combination treatment of AF and cold atmospheric plasma both reduced tumor growth kinetics and prolonged survival in GBM-bearing mice. Thus, our study provides a novel therapeutic strategy for GBM to enhance the efficacy of oxidative stress-inducing therapy through a combination of AF and cold atmospheric plasma.
Topics: Animals; Antioxidants; Apoptosis; Auranofin; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Ferroptosis; Glioblastoma; Humans; Immunogenic Cell Death; Kinetics; Mice, Inbred C57BL; Plasma Gases; Spheroids, Cellular; Mice
PubMed: 34831159
DOI: 10.3390/cells10112936 -
Nature Communications Mar 2017Exploitation of drug-drug synergism and allostery could yield superior therapies by capitalizing on the immensely diverse, but highly specific, potential associated with...
Exploitation of drug-drug synergism and allostery could yield superior therapies by capitalizing on the immensely diverse, but highly specific, potential associated with the biological macromolecular landscape. Here we describe a drug-drug synergy mediated by allosteric cross-talk in chromatin, whereby the binding of one drug alters the activity of the second. We found two unrelated drugs, RAPTA-T and auranofin, that yield a synergistic activity in killing cancer cells, which coincides with a substantially greater number of chromatin adducts formed by one of the compounds when adducts from the other agent are also present. We show that this occurs through an allosteric mechanism within the nucleosome, whereby defined histone adducts of one drug promote reaction of the other drug at a distant, specific histone site. This opens up possibilities for epigenetic targeting and suggests that allosteric modulation in nucleosomes may have biological relevance and potential for therapeutic interventions.
Topics: Allosteric Regulation; Auranofin; Cell Death; Cell Line, Tumor; Chromatin; Crystallography, X-Ray; Drug Synergism; Histones; Humans; Models, Molecular; Nucleic Acid Conformation; Nucleosomes; Organometallic Compounds; Protein Structure, Secondary
PubMed: 28358030
DOI: 10.1038/ncomms14860 -
Chemical Research in Toxicology Jun 2019Phosphine (PH) poisoning continues to be a serious problem worldwide, for which there is no antidote currently available. An invertebrate model for examining potential...
Phosphine (PH) poisoning continues to be a serious problem worldwide, for which there is no antidote currently available. An invertebrate model for examining potential toxicants and their putative antidotes has been used to determine if a strategy of using Au(I) complexes as phosphine-scavenging compounds may be antidotally beneficial. When Galleria mellonella larvae (or wax worms) were subjected to phosphine exposures of 4300 (±700) ppm·min over a 20 min time span, they became immobile (paralyzed) for ∼35 min. The administration of Au(I) complexes auro-sodium bisthiosulfate (AuTS), aurothioglucose (AuTG), and sodium aurothiomalate (AuTM) 5 min prior to phosphine exposure resulted in a drastic reduction in the recovery time (0-4 min). When the putative antidotes were given 10 min after the phosphine exposure, all the antidotes were therapeutic, resulting in mean recovery times of 14, 17, and 19 min for AuTS, AuTG, and AuTM, respectively. Since AuTS proved to be the best therapeutic agent in the G. mellonella model, it was subsequently tested in mice using a behavioral assessment (pole-climbing test). Mice given AuTS (50 mg/kg) 5 min prior to a 3200 (±500) ppm·min phosphine exposure exhibited behavior comparable to mice not exposed to phosphine. However, when mice were given a therapeutic dose of AuTS (50 mg/kg) 1 min after a similar phosphine exposure, only a very modest improvement in performance was observed.
Topics: Animals; Antidotes; Larva; Male; Mice; Moths; Organogold Compounds; Phosphines
PubMed: 31070361
DOI: 10.1021/acs.chemrestox.9b00095 -
Journal of Medicinal Chemistry Jun 2022The search for highly selective sensitizers with a novel mechanism for tumor targeting therapy is of considerable interest. In this work, we have developed a series of...
The search for highly selective sensitizers with a novel mechanism for tumor targeting therapy is of considerable interest. In this work, we have developed a series of new biotin-targeted Au(I) complexes. Through systematic biological evaluation and comparison, biotinylated Au(I) complex containing a triphenylphosphine ligand was screened, as it realized both prominent efficient inhibition and selective cytotoxicity to cancer cells, and the effect was better than that of popularly used auranofin. Meanwhile, complex , as a potent radiosensitizer, enhances anticancer effects and and has sensitization selectivity. From the action mechanism study, we provide evidence that complex could intervene in redox homeostasis through targeted binding and strong suppression of thioredoxin reductase (TrxR) and induce the ferroptosis death process, enabling it to sensitize tumor cells to radiotherapy. Thus, complex has enormous potential as an efficient and specific radiosensitizing agent in cancer therapy.
Topics: Antineoplastic Agents; Auranofin; Biotin; Cell Line, Tumor; Ferroptosis; Homeostasis; Neoplasms; Oxidation-Reduction; Radiation-Sensitizing Agents; Thioredoxin-Disulfide Reductase
PubMed: 35687871
DOI: 10.1021/acs.jmedchem.2c00300 -
Molecules (Basel, Switzerland) Jul 2015The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide disulfide oxidoreductases playing a central role in cellular redox... (Review)
Review
The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide disulfide oxidoreductases playing a central role in cellular redox homeostasis and signaling pathways. Recently, these selenoproteins have emerged as promising therapeutic targets for anticancer drug development, often being overexpressed in tumor cells and contributing to drug resistance. Herein, we summarize the current knowledge on metal- and semimetal-containing molecules capable of hampering mammalian TrxRs, with an emphasis on compounds reported in the last decade.
Topics: Animals; Antineoplastic Agents; Auranofin; Aurothioglucose; Enzyme Inhibitors; Humans; Isoenzymes; Models, Molecular; Neoplasm Proteins; Neoplasms; Organoplatinum Compounds; Oxidative Stress; Phosphines; Ruthenium Compounds; Thioredoxin-Disulfide Reductase
PubMed: 26184149
DOI: 10.3390/molecules200712732