-
Frontiers in Oncology 2021Colon cancer is one of the deadliest tumors in the world, and with high metastasis rate and mortality, effective drugs for its treatment are still in need. Auranofin...
Colon cancer is one of the deadliest tumors in the world, and with high metastasis rate and mortality, effective drugs for its treatment are still in need. Auranofin (AF) is a gold complex that has been attested by FDA for treating human rheumatism, and researchers have found that AF acts as a great antitumor drug in recent years. ICG-001 is a small molecule inhibitor of Wnt/β-catenin pathway. In the present study, we aimed to explore the synergistic antitumor effects and the underlying mechanisms of AF and ICG-001 combination therapy on human colon cancer. The results showed that AF and ICG-001 synergistically depressed the growth and invasion of human colon cancer cells by inhibiting the phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) and its downstream mediator B-cell lymphoma-2-like 1 (Bcl-xL) and inducing caspase-3-dependent apoptosis. Moreover, AF combined with ICG-001 synergistically inhibited the growth of colon cancer in subcutaneous xenograft mice models and restrained metastasis in lung metastasis mice models. In conclusion, our results demonstrated that combination of AF and ICG-001 suppressed the proliferation and metastasis of colon cancer by inhibiting STAT3 phosphorylation. Therefore, this combination therapy may possess potential therapeutic properties for human colon cancer.
PubMed: 34900688
DOI: 10.3389/fonc.2021.738085 -
BioRxiv : the Preprint Server For... May 2024Novel therapeutic approaches are needed for the treatment of Ewing sarcoma tumors. We previously identified that Ewing sarcoma cell lines are sensitive to drugs that...
Novel therapeutic approaches are needed for the treatment of Ewing sarcoma tumors. We previously identified that Ewing sarcoma cell lines are sensitive to drugs that inhibit protein translation. However, translational and therapeutic approaches to inhibit protein synthesis in tumors are limited. In this work, we identified that reactive oxygen species, which are generated by a wide range of chemotherapy and other drugs, inhibit protein synthesis and reduce the level of critical proteins that support tumorigenesis in Ewing sarcoma cells. In particular, we identified that both hydrogen peroxide and auranofin, an inhibitor of thioredoxin reductase and regulator of oxidative stress and reactive oxygen species, activate the repressor of protein translation 4E-BP1 and reduce the levels of the oncogenic proteins RRM2 and PLK1 in Ewing and other sarcoma cell lines. These results provide novel insight into the mechanism of how ROS-inducing drugs target cancer cells via inhibition of protein translation and identify a mechanistic link between ROS and the DNA replication (RRM2) and cell cycle regulatory (PLK1) pathways.
PubMed: 38798568
DOI: 10.1101/2024.05.13.593567 -
Antioxidants (Basel, Switzerland) May 2022Pancreatic cancer accounts for nearly one fourth of all new cancers worldwide. Little progress in the development of novel or adjuvant therapies has been made over the... (Review)
Review
Pancreatic cancer accounts for nearly one fourth of all new cancers worldwide. Little progress in the development of novel or adjuvant therapies has been made over the past few decades and new approaches to the treatment of pancreatic cancer are desperately needed. Pharmacologic ascorbate (P-AscH, high-dose, intravenous vitamin C) is being investigated in clinical trials as an adjunct to standard-of-care chemoradiation treatments. In vitro, P-AscH has been shown to sensitize cancer cells to ionizing radiation in a manner that is dependent on the generation of HO while simultaneously protecting normal tissue from radiation damage. There is renewed interest in Auranofin (Au), an FDA-approved medication utilized in the treatment of rheumatoid arthritis, as an anti-cancer agent. Au inhibits the thioredoxin antioxidant system, thus increasing the overall peroxide burden on cancer cells. In support of current literature demonstrating Au's effectiveness in breast, colon, lung, and ovarian cancer, we offer additional data that demonstrate the effectiveness of Au alone and in combination with P-AscH and ionizing radiation in pancreatic cancer treatment. Combining P-AscH and Au in the treatment of pancreatic cancer may confer multiple mechanisms to increase HO-dependent toxicity amongst cancer cells and provide a promising translatable avenue by which to enhance radiation effectiveness and improve patient outcomes.
PubMed: 35624835
DOI: 10.3390/antiox11050971 -
Inorganic Chemistry Feb 2019Inspired by the preferential, allosteric binding of RAPTA-T and auranofin to the nucleosome core particle , we describe the design and synthesis of a series of...
Inspired by the preferential, allosteric binding of RAPTA-T and auranofin to the nucleosome core particle , we describe the design and synthesis of a series of heterobimetallic ruthenium(II)-gold(I) complexes with varying spacer lengths ranging from four to eight polyethylene glycol units. Evaluation of their cytotoxicity reveals IC values in the low micromolar range against cisplatin sensitive and resistant human ovarian carcinoma (A2780, A2780cisR) and nontumoral human embryonic kidney (HEK293) cell lines. Binding studies monitored via mass spectrometry revealed an affinity for histidine residues on a fragment of the amyloid β-protein (residues 1-16, employed as a model system), which is in accordance with the binding sites of parent drugs, RAPTA-C and auranofin, to the nucleosome core particle.
Topics: Coordination Complexes; Gold; Histidine; Peptides; Ruthenium
PubMed: 30730132
DOI: 10.1021/acs.inorgchem.8b03069 -
Chemical Reviews May 2023The gold drugs, gold sodium thiomalate (Myocrisin), aurothioglucose (Solganal), and the orally administered auranofin (Ridaura), are utilized in modern medicine for the... (Review)
Review
The gold drugs, gold sodium thiomalate (Myocrisin), aurothioglucose (Solganal), and the orally administered auranofin (Ridaura), are utilized in modern medicine for the treatment of inflammatory arthritis including rheumatoid and juvenile arthritis; however, new gold agents have been slow to enter the clinic. Repurposing of auranofin in different disease indications such as cancer, parasitic, and microbial infections in the clinic has provided impetus for the development of new gold complexes for biomedical applications based on unique mechanistic insights differentiated from auranofin. Various chemical methods for the preparation of physiologically stable gold complexes and associated mechanisms have been explored in biomedicine such as therapeutics or chemical probes. In this Review, we discuss the chemistry of next generation gold drugs, which encompasses oxidation states, geometry, ligands, coordination, and organometallic compounds for infectious diseases, cancer, inflammation, and as tools for chemical biology via gold-protein interactions. We will focus on the development of gold agents in biomedicine within the past decade. The Review provides readers with an accessible overview of the utility, development, and mechanism of action of gold-based small molecules to establish context and basis for the thriving resurgence of gold in medicine.
Topics: Humans; Auranofin; Arthritis, Rheumatoid; Anti-Inflammatory Agents; Gold; Aurothioglucose; Gold Sodium Thiomalate
PubMed: 37071737
DOI: 10.1021/acs.chemrev.2c00649 -
Frontiers in Cellular and Infection... 2023Microbe entry through catheter ports can lead to biofilm accumulation and complications from catheter-related bloodstream infection and ultimately require antimicrobial...
Microbe entry through catheter ports can lead to biofilm accumulation and complications from catheter-related bloodstream infection and ultimately require antimicrobial treatment and catheter replacement. Although strides have been made with microbial prevention by applying standardized antiseptic techniques during catheter implantation, both bacterial and fungal microbes can present health risks to already sick individuals. To reduce microbial adhesion, murine and human catheters were coated with polyurethane and auranofin using a dip coating method and compared to non-coated materials. Upon passage of fluid through the coated material , flow dynamics were not impacted. The unique antimicrobial properties of the coating material auranofin has shown inhibitory activity against bacteria such as and fungi such as . Auranofin coating on catheters at 10mg/mL reduced . accumulation from 2.0 x 10 to 7.8 x 10 CFU for mouse catheters and from 1.6 x 10 to 2.8 x 10 for human catheters, showing an impact to mature biofilms. Assessment of a dual microbe biofilm on auranofin-coated catheters resulted in a 2-log reduction in . and a 3-log reduction in . compared to uncoated catheters. assessment in a murine subcutaneous model demonstrated that catheters coated with 10 mg/mL auranofin reduced independent . and . accumulation by 4-log and 1-log, respectively, compared to non-coated catheters. In conclusion, the auranofin-coated catheters demonstrate proficiency at inhibiting multiple pathogens by decreasing . and . biofilm accumulation.
Topics: Humans; Animals; Mice; Auranofin; Staphylococcus aureus; Bacteria; Biofilms; Candida albicans; Catheters
PubMed: 37313344
DOI: 10.3389/fcimb.2023.1135942 -
Pharmaceutics May 2021Auranofin (AF) and its iodido analog, i.e., Au(PEt) I (AFI), were reported to exhibit very promising anticancer properties both in vitro and in vivo. However, both these...
Auranofin (AF) and its iodido analog, i.e., Au(PEt) I (AFI), were reported to exhibit very promising anticancer properties both in vitro and in vivo. However, both these gold compounds have a scarce aqueous solubility that hampers their pharmaceutical use. Here, we explore whether encapsulation of these metallodrugs inside hydroxypropyl-beta-cyclodextrin (HPβ-CD) may lead to an improved biopharmaceutical profile for the resulting adducts. Phase solubility studies, performed at 25 °C in an aqueous buffer, revealed, in both cases, the formation of a 1:1 drug to cyclodextrin complex; a far greater apparent stability constant (K) was measured for AFI compared to AF (331 M versus ca. 30 M). NMR studies conducted on the AFI/HPβ-CD system confirmed the formation of a stable 1:1 adduct. Then, binary systems of AF and AFI with HPβ-CD were prepared by colyophilization and characterized by DSC and PXRD. The results revealed the occurrence of drug complexation and/or amorphization for the AFI/HPβ-CD binary system. Afterwards, the antiproliferative properties of the two cyclodextrin adducts and of the corresponding free drugs were comparatively evaluated in vitro in three representative ovarian cancer cell lines, i.e., A2780, SKOV3, and IGROV-1. The results, in all cases, point out that CD complexation of the two gold drugs does not substantially affect their biological activity. The implications of these findings are discussed in the frame of the current knowledge of AF and its analogs.
PubMed: 34063389
DOI: 10.3390/pharmaceutics13050727 -
Discover Oncology Oct 2021Advanced stages of cancer are highly associated with short overall survival in patients due to the lack of long-term treatment options following the standard form of... (Review)
Review
Advanced stages of cancer are highly associated with short overall survival in patients due to the lack of long-term treatment options following the standard form of care. New options for cancer therapy are needed to improve the survival of cancer patients without disease recurrence. Auranofin is a clinically approved agent against rheumatoid arthritis that is currently enrolled in clinical trials for potential repurposing against cancer. Auranofin mainly targets the anti-oxidative system catalyzed by thioredoxin reductase (TrxR), which protects the cell from oxidative stress and death in the cytoplasm and the mitochondria. TrxR is over-expressed in many cancers as an adaptive mechanism for cancer cell proliferation, rendering it an attractive target for cancer therapy, and auranofin as a potential therapeutic agent for cancer. Inhibiting TrxR dysregulates the intracellular redox state causing increased intracellular reactive oxygen species levels, and stimulates cellular demise. An alternate mechanism of action of auranofin is to mimic proteasomal inhibition by blocking the ubiquitin-proteasome system (UPS), which is critically important in cancer cells to prevent cell death when compared to non-cancer cells, because of its role on cell cycle regulation, protein degradation, gene expression, and DNA repair. This article provides new perspectives on the potential mechanisms used by auranofin alone, in combination with diverse other compounds, or in combination with platinating agents and/or immune checkpoint inhibitors to combat cancer cells, while assessing the feasibility for its repurposing in the clinical setting.
PubMed: 35201489
DOI: 10.1007/s12672-021-00439-0 -
Frontiers in Cellular and Infection... 2019Intravascular catheter related bloodstream infections (CRBSIs) are a leading cause of hospital-acquired infections worldwide, resulting not only in the burden of cost...
Intravascular catheter related bloodstream infections (CRBSIs) are a leading cause of hospital-acquired infections worldwide, resulting not only in the burden of cost and morbidity for patients but also in the over-consumption of medical resources for hospitals and health care organizations. In this study, a novel auranofin releasing antibacterial and antibiofilm polyurethane (PU) catheter coating was developed and investigated for future use in preventing CRBSIs. Auranofin is an antirheumatic drug with recently identified antimicrobial properties. The drug carrier, PU, acts as a barrier surrounding the antibacterial agent, auranofin, to extend the drug release profile and improve its long-term antibacterial and antibiofilm efficacy and potentially the length of catheter implantation within a patient. The PU+auranofin coatings developed here were found to be highly stretchable (exhibiting ~500% percent elongation), which is important for the compliance of the material on a flexible catheter. PU+auranofin coated catheters were able to inhibit the growth of methicillin-resistant (MRSA) for 8 to 26 days depending on the specific drug concentration utilized during the dip coating process. The PU+auranofin coated catheters were also able to completely inhibit MRSA biofilm formation , an effect that was not observed with auranofin or PU alone. Lastly, these coatings were found to be hemocompatible with human erythrocytes and maintain liver cell viability.
Topics: Anti-Infective Agents; Auranofin; Biofilms; Catheters; Chemical Phenomena; Coated Materials, Biocompatible; Drug Carriers; Methicillin-Resistant Staphylococcus aureus; Polyurethanes
PubMed: 30873389
DOI: 10.3389/fcimb.2019.00037 -
Cancer Metastasis Reviews Dec 2017Deubiquitinases (DUBs) play an important role in protein quality control in eukaryotic cells due to their ability to specifically remove ubiquitin from substrate... (Review)
Review
Deubiquitinases (DUBs) play an important role in protein quality control in eukaryotic cells due to their ability to specifically remove ubiquitin from substrate proteins. Therefore, recent findings have focused on the relevance of DUBs to cancer development, and pharmacological intervention on these enzymes has become a promising strategy for cancer therapy. In particular, several DUBs are physically and/or functionally associated with the proteasome and are attractive targets for the development of novel anticancer drugs. The successful clinical application of cisplatin in cancer treatment has prompted researchers to develop various metal-based anticancer agents with new properties. Recently, we have reported that several metal-based drugs, such as the antirheumatic gold agent auranofin (AF), the antifouling paint biocides copper pyrithione (CuPT) and zinc pyrithione (ZnPT), and also our two synthesized complexes platinum pyrithione (PtPT) and nickel pyrithione (NiPT), can target the proteasomal DUBs UCHL5 and USP14. In this review, we summarize the recently reported small molecule inhibitors of proteasomal DUBs, with a focus on discussion of the unique nature of metal-based proteasomal DUB inhibitors and their anticancer activity.
Topics: Animals; Antineoplastic Agents; Deubiquitinating Enzymes; Humans; Neoplasms; Organometallic Compounds; Proteasome Inhibitors; Small Molecule Libraries
PubMed: 29039082
DOI: 10.1007/s10555-017-9701-1