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Nature Communications Aug 2023UBA1 is the primary E1 ubiquitin-activating enzyme responsible for generation of activated ubiquitin required for ubiquitination, a process that regulates stability and...
UBA1 is the primary E1 ubiquitin-activating enzyme responsible for generation of activated ubiquitin required for ubiquitination, a process that regulates stability and function of numerous proteins. Decreased or insufficient ubiquitination can cause or drive aging and many diseases. Therefore, a small-molecule enhancing UBA1 activity could have broad therapeutic potential. Here we report that auranofin, a drug approved for the treatment of rheumatoid arthritis, is a potent UBA1 activity enhancer. Auranofin binds to the UBA1's ubiquitin fold domain and conjugates to Cys1039 residue. The binding enhances UBA1 interactions with at least 20 different E2 ubiquitin-conjugating enzymes, facilitating ubiquitin charging to E2 and increasing the activities of seven representative E3s in vitro. Auranofin promotes ubiquitination and degradation of misfolded ER proteins during ER-associated degradation in cells at low nanomolar concentrations. It also facilitates outer mitochondrial membrane-associated degradation. These findings suggest that auranofin can serve as a much-needed tool for UBA1 research and therapeutic exploration.
Topics: Ubiquitin; Ubiquitin-Conjugating Enzymes; Auranofin; Ubiquitination; Ubiquitin-Activating Enzymes
PubMed: 37558718
DOI: 10.1038/s41467-023-40537-x -
Journal of Hematology & Oncology Nov 2023T-cell acute lymphoblastic leukemia (T-ALL) is a type of hematologic tumor with malignant proliferation of hematopoietic progenitor cells. However, traditional clinical...
T-cell acute lymphoblastic leukemia (T-ALL) is a type of hematologic tumor with malignant proliferation of hematopoietic progenitor cells. However, traditional clinical treatment of T-ALL included chemotherapy and stem cell transplantation always lead to recurrence and poor prognosis, thus new therapeutic targets and drugs are urgently needed for T-ALL treatment. In this study, we showed that TET1 (ten-eleven translocation 1), a key participant of DNA epigenetic control, which catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to modulate gene expression, was highly upregulated in human T-ALL and negatively correlated with the prognosis of patients. Knockdown of TET1 suppressed T-ALL growth and progression, suggesting that TET1 inhibition maybe an effective way to fight T-ALL via DNA epigenetic modulation. Combining structure-guided virtual screening and cell-based high-throughput screening of FDA-approved drug library, we discovered that auranofin, a gold-containing compound, is a potent TET1 inhibitor. Auranofin inhibited the catalytic activity of TET1 through competitive binding to its substrates binding pocket and thus downregulated the genomic level of 5hmC marks and particularly epigenetically reprogramed the expression of oncogene c-Myc in T-ALL in TET1-dependent manner and resulted in suppression of T-ALL in vitro and in vivo. These results revealed that TET1 is a potential therapeutic target in human T-ALL and elucidated the mechanism that TET1 inhibitor auranofin suppressed T-ALL through the TET1/5hmC/c-Myc signaling pathway. Our work thus not only provided mechanism insights for T-ALL treatment, but also discovered potential small molecule therapeutics for T-ALL.
Topics: Humans; Proto-Oncogene Proteins; Auranofin; Proto-Oncogene Proteins c-myc; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Dioxygenases; Mixed Function Oxygenases; Signal Transduction; DNA Methylation; DNA; Cell Death; Arthritis, Rheumatoid
PubMed: 37993905
DOI: 10.1186/s13045-023-01513-6 -
Journal of Molecular Medicine (Berlin,... Apr 2024Acute leukemia continues to be a major cause of death from disease worldwide and current chemotherapeutic agents are associated with significant morbidity in survivors....
Acute leukemia continues to be a major cause of death from disease worldwide and current chemotherapeutic agents are associated with significant morbidity in survivors. While better and safer treatments for acute leukemia are urgently needed, standard drug development pipelines are lengthy and drug repurposing therefore provides a promising approach. Our previous evaluation of FDA-approved drugs for their antileukemic activity identified disulfiram, used for the treatment of alcoholism, as a candidate hit compound. This study assessed the biological effects of disulfiram on leukemia cells and evaluated its potential as a treatment strategy. We found that disulfiram inhibits the viability of a diverse panel of acute lymphoblastic and myeloid leukemia cell lines (n = 16) and patient-derived xenograft cells from patients with poor outcome and treatment-resistant disease (n = 15). The drug induced oxidative stress and apoptosis in leukemia cells within hours of treatment and was able to potentiate the effects of daunorubicin, etoposide, topotecan, cytarabine, and mitoxantrone chemotherapy. Upon combining disulfiram with auranofin, a drug approved for the treatment of rheumatoid arthritis that was previously shown to exert antileukemic effects, strong and consistent synergy was observed across a diverse panel of acute leukemia cell lines, the mechanism of which was based on enhanced ROS induction. Acute leukemia cells were more sensitive to the cytotoxic activity of disulfiram than solid cancer cell lines and non-malignant cells. While disulfiram is currently under investigation in clinical trials for solid cancers, this study provides evidence for the potential of disulfiram for acute leukemia treatment. KEY MESSAGES: Disulfiram induces rapid apoptosis in leukemia cells by boosting oxidative stress. Disulfiram inhibits leukemia cell growth more potently than solid cancer cell growth. Disulfiram can enhance the antileukemic efficacy of chemotherapies. Disulfiram strongly synergises with auranofin in killing acute leukemia cells by ROS induction. We propose testing of disulfiram in clinical trial for patients with acute leukemia.
Topics: Humans; Disulfiram; Reactive Oxygen Species; Auranofin; Cell Line, Tumor; Leukemia, Myeloid, Acute
PubMed: 38349407
DOI: 10.1007/s00109-023-02414-4 -
Nature Communications Oct 2023Genome-scale metabolic models are widely used to enhance our understanding of metabolic features of organisms, host-pathogen interactions and to identify therapeutics...
Genome-scale metabolic models are widely used to enhance our understanding of metabolic features of organisms, host-pathogen interactions and to identify therapeutics for diseases. Here we present iTMU798, the genome-scale metabolic model of the mouse whipworm Trichuris muris. The model demonstrates the metabolic features of T. muris and allows the prediction of metabolic steps essential for its survival. Specifically, that Thioredoxin Reductase (TrxR) enzyme is essential, a prediction we validate in vitro with the drug auranofin. Furthermore, our observation that the T. muris genome lacks gsr-1 encoding Glutathione Reductase (GR) but has GR activity that can be inhibited by auranofin indicates a mechanism for the reduction of glutathione by the TrxR enzyme in T. muris. In addition, iTMU798 predicts seven essential amino acids that cannot be synthesised by T. muris, a prediction we validate for the amino acid tryptophan. Overall, iTMU798 is as a powerful tool to study not only the T. muris metabolism but also other Trichuris spp. in understanding host parasite interactions and the rationale design of new intervention strategies.
Topics: Animals; Mice; Trichuris; Auranofin; Glutathione; Glutathione Reductase; Host-Pathogen Interactions
PubMed: 37907472
DOI: 10.1038/s41467-023-42552-4 -
International Journal of Biological... 2024Lung cancer is one of the most lethal diseases in the world. Although there has been significant progress in the treatment of lung cancer, there is still a lack of...
Lung cancer is one of the most lethal diseases in the world. Although there has been significant progress in the treatment of lung cancer, there is still a lack of effective strategies for advanced cases. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, has achieved much attention due to its antitumor properties. Nevertheless, the use of lenvatinib is restricted by the characteristics of poor efficacy and drug resistance. In this study, we assessed the effectiveness of lenvatinib combined with thioredoxin reductase 1 (TrxR1) inhibitors in human lung cancer cells. Our results indicate that the combination therapy involving TrxR1 inhibitors and lenvatinib exhibited significant synergistic antitumor effects in human lung cancer cells. Moreover, siTrxR1 also showed significant synergy with lenvatinib in lung cancer cells. Mechanically, we demonstrated that ROS accumulation significantly contributes to the synergism between lenvatinib and TrxR1 inhibitor auranofin. Furthermore, the combination of lenvatinib and auranofin can activate endoplasmic reticulum stress and JNK signaling pathways to achieve the goal of killing lung cancer cells. Importantly, combination therapy with lenvatinib and auranofin exerted a synergistic antitumor effect . To sum up, the combination therapy involving lenvatinib and auranofin may be a potential strategy for treating lung cancer.
Topics: Humans; Thioredoxin Reductase 1; Lung Neoplasms; Reactive Oxygen Species; Auranofin; Apoptosis; Cell Line, Tumor; Cell Death
PubMed: 38164168
DOI: 10.7150/ijbs.86160 -
Microbiology Spectrum Feb 2024Auranofin, an FDA-approved drug for rheumatoid arthritis, has emerged as a promising antiparasitic medication in recent years. The gold(I) ion in auranofin is postulated...
Auranofin, an FDA-approved drug for rheumatoid arthritis, has emerged as a promising antiparasitic medication in recent years. The gold(I) ion in auranofin is postulated to be responsible for its antiparasitic activity. Notably aurothiomalate and aurothioglucose also contain gold(I), and, like auranofin, they were previously used to treat rheumatoid arthritis. Whether they have antiparasitic activity remains to be elucidated. Herein, we demonstrated that auranofin and similar derivatives, but not aurothiomalate and aurothioglucose, inhibited the growth of . We found that auranofin affected the biological cycle (lytic cycle) by inhibiting invasion and triggering its egress from the host cell. However, auranofin could not prevent parasite replication once resided within the host. Auranofin treatment induced apoptosis in parasites as demonstrated by its reduced size and elevated phosphatidylserine externalization (PS). Notably, the gold from auranofin enters the cytoplasm of as demonstrated by scanning transmission electron microscopy-energy dispersive X-ray spectroscopy (STEM-EDS) and Inductively Coupled Plasma-Mass Spectrometry (ICP-MS).IMPORTANCEToxoplasmosis, caused by , is a devastating disease affecting the brain and the eyes, frequently affecting immunocompromised individuals. Approximately 60 million people in the United States are already infected with , representing a population at-risk of developing toxoplasmosis. Recent advances in treating cancer, autoimmune diseases, and organ transplants have contributed to this at-risk population's exponential growth. Paradoxically, treatments for toxoplasmosis have remained the same for more than 60 years, relying on medications well-known for their bone marrow toxicity and allergic reactions. Discovering new therapies is a priority, and repurposing FDA-approved drugs is an alternative approach to speed up drug discovery. Herein, we report the effect of auranofin, an FDA-approved drug, on the biological cycle of and how both the phosphine ligand and the gold molecule determine the anti-parasitic activity of auranofin and other gold compounds. Our studies would contribute to the pipeline of candidate anti- agents.
Topics: Humans; Auranofin; Gold; Toxoplasma; Ligands; Aurothioglucose; Arthritis, Rheumatoid; Gold Sodium Thiomalate; Toxoplasmosis; Antiparasitic Agents; Phosphines
PubMed: 38206030
DOI: 10.1128/spectrum.02968-23 -
Molecules (Basel, Switzerland) Jul 2023Gold 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... (Review)
Review
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)]PF, 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.
Topics: Gold Compounds; Gold; Auranofin; Antineoplastic Agents; Thioredoxin-Disulfide Reductase
PubMed: 37446857
DOI: 10.3390/molecules28135196 -
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 -
Nature Communications May 2024Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i's) in combination with chemotherapy have shown promising...
Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i's) in combination with chemotherapy have shown promising results in preclinical studies but have displayed minimal efficacy with substantial toxicity in clinical trials. To explore combinatorial strategies that can overcome these limitations, we perform an unbiased high-throughput screen in a non-small cell lung cancer (NSCLC) cell line and identify thioredoxin1 (Trx1), a major component of the mammalian antioxidant-system, as a determinant of CHK1i sensitivity. We establish a role for redox recycling of RRM1, the larger subunit of ribonucleotide reductase (RNR), and a depletion of the deoxynucleotide pool in this Trx1-mediated CHK1i sensitivity. Further, the TrxR inhibitor auranofin, an approved anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, we show a pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity.
Topics: Checkpoint Kinase 1; Humans; Oxidation-Reduction; Thioredoxins; Cell Line, Tumor; Auranofin; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Protein Kinase Inhibitors; Ribonucleoside Diphosphate Reductase; Ribonucleotide Reductases; Drug Synergism; Animals
PubMed: 38821952
DOI: 10.1038/s41467-024-48076-9 -
Journal of Inorganic Biochemistry Feb 2024Three gold(I) linear compounds, sharing the general formula [AuI(LPh)], have been synthesized and characterized. The nature of the ligand has been modified by moving...
Three gold(I) linear compounds, sharing the general formula [AuI(LPh)], have been synthesized and characterized. The nature of the ligand has been modified by moving down among some of the elements of group 15, i.e. phosphorus, arsenic and antimony. The structures of derived compounds have been solved through XRD and the reactivity behaviour towards selected biomolecules has been investigated through a multi-technique approach involving NMR, high-resolution mass spectrometry and IR. Moreover, the biological activity of the investigated compounds has been comparatively analyzed through classical methodologies and the disclosed differences are discussed in detail.
Topics: Auranofin; Antimony; Ligands; Antineoplastic Agents
PubMed: 38070433
DOI: 10.1016/j.jinorgbio.2023.112452