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Yakugaku Zasshi : Journal of the... 2021Gold compounds have been employed throughout history to treat various types of disease, from ancient times to the present day. In the year 1985, auranofin, a... (Review)
Review
Gold compounds have been employed throughout history to treat various types of disease, from ancient times to the present day. In the year 1985, auranofin, a gold-containing compound, was approved by U.S. Food and Drug Administration (FDA) as a therapeutic agent to target rheumatoid arthritis that would facilitate easy oral drug administration as opposed to conventional intramuscular injection used in treatments. Furthermore, auranofin demonstrates promising results for the treatment of various diseases beyond rheumatoid arthritis, including cancer, neurodegenerative diseases, acquired immune deficiency syndrome, and bacterial and parasitic infections. Various potential novel applications for auranofin have been proposed for treating human diseases. Auranofin has previously been demonstrated to inhibit thioredoxin reductase (TrxR) involved within the thioredoxin (Trx) system that comprises one of the critical cellular redox systems within the body. TrxR comprises the sole known enzyme that catalyzes Trx reduction. With cancers in particular, TrxR inhibition facilitates an increase in cellular oxidative stress and suppresses tumor growth. In this review, we describe the potential of auranofin to serve as an anticancer agent and further drug repurposing to utilize this as a strategy for further appropriate drug developments.
Topics: Antineoplastic Agents; Arthritis, Rheumatoid; Auranofin; Drug Development; Drug Repositioning; Humans; Neoplasms; Oxidative Stress; Thioredoxin-Disulfide Reductase
PubMed: 33642497
DOI: 10.1248/yakushi.20-00179-2 -
Cancer Drug Resistance (Alhambra,... 2022Today colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. This disease is poorly chemo-sensitive toward the existing medical treatments so... (Review)
Review
Today colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. This disease is poorly chemo-sensitive toward the existing medical treatments so that new and more effective therapeutic agents are urgently needed and intensely sought. Platinum drugs, oxaliplatin in particular, were reported to produce some significant benefit in CRC treatment, triggering the general interest of medicinal chemists and oncologists for metal-based compounds as candidate anti-CRC drugs. Within this frame, gold compounds and, specifically, the established antiarthritic drug auranofin with its analogs, form a novel group of promising anticancer agents. Owing to its innovative mechanism of action and its favorable pharmacological profile, auranofin together with its derivatives are proposed here as novel experimental agents for CRC treatment, capable of overcoming resistance to platinum drugs. Some encouraging results in this direction have already been obtained. A few recent studies demonstrate that the action of auranofin may be further potentiated through the preparation of suitable pharmaceutical formulations capable of protecting the gold pharmacophore from unselective reactivity or through the design of highly synergic drug combinations. The perspectives of the research in this field are outlined.
PubMed: 35582525
DOI: 10.20517/cdr.2021.71 -
Cell Metabolism Dec 2022Low-grade, sustained inflammation in white adipose tissue (WAT) characterizes obesity and coincides with type 2 diabetes mellitus (T2DM). However, pharmacological...
Low-grade, sustained inflammation in white adipose tissue (WAT) characterizes obesity and coincides with type 2 diabetes mellitus (T2DM). However, pharmacological targeting of inflammation lacks durable therapeutic effects in insulin-resistant conditions. Through a computational screen, we discovered that the FDA-approved rheumatoid arthritis drug auranofin improved insulin sensitivity and normalized obesity-associated abnormalities, including hepatic steatosis and hyperinsulinemia in mouse models of T2DM. We also discovered that auranofin accumulation in WAT depleted inflammatory responses to a high-fat diet without altering body composition in obese wild-type mice. Surprisingly, elevated leptin levels and blunted beta-adrenergic receptor activity achieved by leptin receptor deletion abolished the antidiabetic effects of auranofin. These experiments also revealed that the metabolic benefits of leptin reduction were superior to immune impacts of auranofin in WAT. Our studies uncover important metabolic properties of anti-inflammatory treatments and contribute to the notion that leptin reduction in the periphery can be accomplished to treat obesity and T2DM.
Topics: Animals; Mice; Mice, Obese; Hypoglycemic Agents; Auranofin; Diabetes Mellitus, Type 2; Arthritis, Rheumatoid; Obesity
PubMed: 36243005
DOI: 10.1016/j.cmet.2022.09.019 -
Contemporary Oncology (Poznan, Poland) 2015Worldwide research groups are searching for anticancer compounds, many of them are organometalic complexes having platinum group metals as their active centers. Most... (Review)
Review
Worldwide research groups are searching for anticancer compounds, many of them are organometalic complexes having platinum group metals as their active centers. Most commonly used cytostatics from this group are cisplatin, carboplatin and oxaliplatin. Cisplatin was used fot the first time in 1978, from this time many platinum derivatives were created. In this review we present biological properties and probable future clinical use of platinum, gold, silver, iridium and ruthenium derivatives. Gold derivative Auranofin has been studied extensively. Action of silver nanoparticles on different cell lines was analysed. Iridium isotopes are commonly used in brachyterapy. Ruthenium compound new anti-tumour metastasis inhibitor (NAMI-A) is used in managing lung cancer metastases. Electroporation of another ruthenium based compound KP1339 was also studied. Most of described complexes have antiproliferative and proapoptotic properties. Further studies need to be made. Nevertheless noble metal based chemotherapheutics and compounds seem to be an interesting direction of research.
PubMed: 26557773
DOI: 10.5114/wo.2015.54386 -
Antibiotics (Basel, Switzerland) Mar 2023The necessity for the discovery of innovative antimicrobials to treat life-threatening diseases has increased as multidrug-resistant bacteria has spread. Due to... (Review)
Review
The necessity for the discovery of innovative antimicrobials to treat life-threatening diseases has increased as multidrug-resistant bacteria has spread. Due to antibiotics' availability over the counter in many nations, antibiotic resistance is linked to overuse, abuse, and misuse of these drugs. The World Health Organization (WHO) recognized 12 families of bacteria that present the greatest harm to human health, where options of antibiotic therapy are extremely limited. Therefore, this paper reviews possible new ways for the development of novel classes of antibiotics for which there is no pre-existing resistance in human bacterial pathogens. By utilizing research and technology such as nanotechnology and computational methods (such as in silico and Fragment-based drug design (FBDD)), there has been an improvement in antimicrobial actions and selectivity with target sites. Moreover, there are antibiotic alternatives, such as antimicrobial peptides, essential oils, anti-Quorum sensing agents, darobactins, vitamin B6, bacteriophages, odilorhabdins, 18β-glycyrrhetinic acid, and cannabinoids. Additionally, drug repurposing (such as with ticagrelor, mitomycin C, auranofin, pentamidine, and zidovudine) and synthesis of novel antibacterial agents (including lactones, piperidinol, sugar-based bactericides, isoxazole, carbazole, pyrimidine, and pyrazole derivatives) represent novel approaches to treating infectious diseases. Nonetheless, prodrugs (e.g., siderophores) have recently shown to be an excellent platform to design a new generation of antimicrobial agents with better efficacy against multidrug-resistant bacteria. Ultimately, to combat resistant bacteria and to stop the spread of resistant illnesses, regulations and public education regarding the use of antibiotics in hospitals and the agricultural sector should be combined with research and technological advancements.
PubMed: 36978495
DOI: 10.3390/antibiotics12030628 -
Oncoscience 2015Copper and gold complexes have clinical activity in several diseases including cancer. Recently, we have reported that the anti-cancer activity of copper (II) pyrithione... (Review)
Review
Copper and gold complexes have clinical activity in several diseases including cancer. Recently, we have reported that the anti-cancer activity of copper (II) pyrithione CuPT and gold (I) complex auranofin is associated with targeting the 19S proteasome-associated deubiquitinases (DUBs), UCHL5 and USP14. Here we discuss metal DUB inhibitors in treating cancer and other diseases. (from Editor). Several copper and gold complexes have clinical activity in treating some human diseases including cancer. Recently, we have reported that the anti-cancer activity of copper (II) pyrithione CuPT and gold (I) complex auranofin is tightly associated with their ability to target and inhibit the 19S proteasome-associated deubiquitinases (DUBs), UCHL5 and USP14. In this article we review small molecule inhibitors of DUBs and 19S proteasome-associated DUBs. We then describe and discuss the ubique nature of CuPT and auranofin, which is inhibition of 19S proteasome-associated UCHL5 and USP14. We finally suggest the potential to develop novel, specific metal-based DUB inhibitors for treating cancer and other diseases.
PubMed: 26097878
DOI: 10.18632/oncoscience.167 -
Cancer Research Apr 2021is amplified in 20% to 25% of neuroblastoma, and -amplified neuroblastoma contributes to a large percent of pediatric cancer-related deaths. Therapy improvements for...
is amplified in 20% to 25% of neuroblastoma, and -amplified neuroblastoma contributes to a large percent of pediatric cancer-related deaths. Therapy improvements for this subtype of cancer are a high priority. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1. Accumulating iron causes reactive oxygen species (ROS) production, and -amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. This dependence creates a marked vulnerability to targeting the system Xc-/glutathione (GSH) pathway with ferroptosis inducers. This reliance can be exploited through therapy with FDA-approved rheumatoid arthritis drugs sulfasalazine (SAS) and auranofin: in -amplified, patient-derived xenograft models, both therapies blocked growth and induced ferroptosis. SAS and auranofin activity was largely mitigated by the ferroptosis inhibitor ferrostatin-1, antioxidants like N-acetyl-L-cysteine, or by the iron scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking increased iron capture in -amplified neuroblastoma to a therapeutic vulnerability to ROS-inducing drugs. These data uncover an oncogene vulnerability to ferroptosis caused by increased iron accumulation and subsequent reliance on the system Xc-/GSH pathway. SIGNIFICANCE: This study shows how MYCN increases intracellular iron levels and subsequent GSH pathway activity and demonstrates the antitumor activity of FDA-approved SAS and auranofin in patient-derived xenograft models of -amplified neuroblastoma.
Topics: Animals; Antioxidants; Auranofin; Cell Line, Tumor; Cell Proliferation; Cell Survival; Child; Enzyme Inhibitors; Ferroptosis; Gene Amplification; Gene Expression Regulation, Enzymologic; Glutathione; Humans; Iron; Male; Mice; Mice, Inbred NOD; Mice, Transgenic; N-Myc Proto-Oncogene Protein; Neuroblastoma; Oxazoles; Phospholipid Hydroperoxide Glutathione Peroxidase; Piperazines; Sulfasalazine; Xenograft Model Antitumor Assays
PubMed: 33483374
DOI: 10.1158/0008-5472.CAN-20-1641 -
Molecules (Basel, Switzerland) May 2023Advanced mesothelioma is considered an incurable disease and new treatment strategies are needed. Previous studies have demonstrated that mitochondrial antioxidant...
Advanced mesothelioma is considered an incurable disease and new treatment strategies are needed. Previous studies have demonstrated that mitochondrial antioxidant defense proteins and the cell cycle may contribute to mesothelioma growth, and that the inhibition of these pathways may be effective against this cancer. We demonstrated that the antioxidant defense inhibitor auranofin and the cyclin-dependent kinase 4/6 inhibitor palbociclib could decrease mesothelioma cell proliferation alone or in combination. In addition, we determined the effects of these compounds on colony growth, cell cycle progression, and the expression of key antioxidant defense and cell cycle proteins. Auranofin and palbociclib were effective in decreasing cell growth and inhibiting the above-described activity across all assays. Further study of this drug combination will elucidate the contribution of these pathways to mesothelioma activity and may reveal a new treatment strategy.
Topics: Humans; Antioxidants; Auranofin; Mesothelioma, Malignant; Mesothelioma; Cell Proliferation; Cyclin-Dependent Kinase 4; Protein Kinase Inhibitors; Cell Line, Tumor
PubMed: 37298855
DOI: 10.3390/molecules28114380 -
Journal of Cellular Physiology Oct 2021Transition metals refer to the elements in the d and ds blocks of the periodic table. Since the success of cisplatin and auranofin, transition metal-based compounds have... (Review)
Review
Transition metals refer to the elements in the d and ds blocks of the periodic table. Since the success of cisplatin and auranofin, transition metal-based compounds have become a prospective source for drug development, particularly in cancer treatment. In recent years, extensive studies have shown that numerous transition metal-based compounds could modulate autophagy, promising a new therapeutic strategy for metal-related diseases and the design of metal-based agents. Copper, zinc, and manganese, which are common components in physiological pathways, play important roles in the progression of cancer, neurodegenerative diseases, and cardiovascular diseases. Furthermore, enrichment of copper, zinc, or manganese can regulate autophagy. Thus, we summarized the current advances in elucidating the mechanisms of some metals/metal-based compounds and their functions in autophagy regulation, which is conducive to explore the intricate roles of autophagy and exploit novel therapeutic drugs for human diseases.
Topics: Animals; Autophagy; Cardiovascular Diseases; Coordination Complexes; Humans; Metals; Neoplasms; Neurodegenerative Diseases; Transition Elements
PubMed: 33694161
DOI: 10.1002/jcp.30359 -
The Journal of Antimicrobial... Feb 2020Clostridioides difficile (previously Clostridium difficile) is the leading cause of nosocomial, antibiotic-associated diarrhoea worldwide. Currently, the gold standard...
BACKGROUND
Clostridioides difficile (previously Clostridium difficile) is the leading cause of nosocomial, antibiotic-associated diarrhoea worldwide. Currently, the gold standard of treatment for C. difficile infection (CDI) is vancomycin or metronidazole, although these antibiotics also perturb the protective resident microbiota, often resulting in disease relapse. Thus, an urgent need remains for the development of new treatment strategies. Auranofin is an FDA-approved oral antirheumatic drug that was previously shown to inhibit C. difficile vegetative cell growth, toxin production and spore production in vitro.
OBJECTIVES
To determine the efficacy of auranofin as a CDI therapeutic by examining the effect of treatment on toxin and spore production in vitro and in vivo, and on disease outcomes in mice.
METHODS
C. difficile cultures were treated with auranofin and examined for effects on sporulation and toxin production by sporulation assay and ELISA, respectively. Mice were pretreated with auranofin prior to infection with C. difficile and monitored for physiological conditions, survival and gut damage compared with control animals. Faeces from mice were analysed to determine whether auranofin reduces sporulation and toxin production in vivo.
RESULTS
Auranofin significantly reduces sporulation and toxin production under in vitro conditions and in infected mice in vivo. Mice treated with auranofin lost less weight, displayed a significant increase in survival rates and had significantly less toxin-mediated damage in their colon and caecum compared with control mice.
CONCLUSIONS
Auranofin shows promise as a prospective therapeutic option for C. difficile infections.
Topics: Animals; Anti-Bacterial Agents; Auranofin; Clostridioides difficile; Clostridium Infections; Drug Repositioning; Mice; Prospective Studies
PubMed: 31642901
DOI: 10.1093/jac/dkz430