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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 -
Anticancer Research Jun 2024Synovial sarcoma (SS) is a rare malignant tumor with a poor survival rate. We previously reported that a combination of auranofin (AUR), a thioredoxin reductase...
BACKGROUND/AIM
Synovial sarcoma (SS) is a rare malignant tumor with a poor survival rate. We previously reported that a combination of auranofin (AUR), a thioredoxin reductase inhibitor, and celecoxib (CE), an anti-inflammatory drug, significantly impedes the local progression of osteosarcoma (OS). However, the role of redox regulation in SS remains to be elucidated. This study aimed to investigate the efficacy of combined treatment of AUR and CE on the local progression of SS in vivo.
MATERIALS AND METHODS
Nu/nu mice were implanted with the human SS cell line, Aska-SS, and treated with vehicle control, AUR, or a combination of AUR and CE (AUR-CE). Primary tumor size and weight were evaluated for the study duration and upon resection, respectively. Hematoxylin and eosin (H&E) and Ki-67 staining were performed to assess the local progression of SS.
RESULTS
A statistically significant reduction in tumor size and weight was observed in the AUR- and AUR-CE-treated groups upon excision compared to that in the vehicle-treated group. The AUR-CE-treated group showed synergistic inhibition of local tumor growth. H&E staining of local SS tumors revealed decreased cell density and nuclear deformation in the AUR- and AUR-CE-treated groups compared to those in the vehicle-treated group. Immunohistochemical staining revealed a statistically significant decrease in Ki-67-positive cells in the AUR-CE-treated group compared to the vehicle-treated group.
CONCLUSION
The combination of AUR and CE showed significant potential for delaying the local progression of SS. These findings support the repurposing of AUR and CE as early treatment options for SS.
Topics: Celecoxib; Animals; Sarcoma, Synovial; Auranofin; Humans; Mice; Disease Progression; Cell Line, Tumor; Xenograft Model Antitumor Assays; Mice, Nude; Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation
PubMed: 38821602
DOI: 10.21873/anticanres.17052 -
Expert Opinion on Drug Discovery Jul 2024Auranofin (AF) is a well-established, FDA-approved, antiarthritic gold drug that is currently being reevaluated for a variety of therapeutic indications through drug... (Review)
Review
INTRODUCTION
Auranofin (AF) is a well-established, FDA-approved, antiarthritic gold drug that is currently being reevaluated for a variety of therapeutic indications through drug repurposing. AF has shown great promise as a potential anticancer agent and has been approved for a few clinical trials in cancer. The renewed interest in AF has led to extensive research into the design, preparation and biological evaluation of auranofin analogs, which may have an even better pharmacological profile than the parent drug.
AREAS COVERED
This article reviews the strategies for chemical modification of the AF scaffold. Several auranofin analogs have been prepared and characterized for medical application in the field of cancer treatment over the last 20 years. Some emerging structure-function relationships are proposed and discussed.
EXPERT OPINION
The chemical modification of the AF scaffold has been the subject of intense activity in recent years and this strategy has led to the preparation and evaluation of several AF analogs. The case of iodauranofin is a particularly promising example. The availability of homogeneous biological data for a group of AF derivatives allows some initial structure-function relationships to be proposed, which may inspire the design and synthesis of new and better AF analogs for cancer treatment.
Topics: Auranofin; Humans; Drug Design; Antineoplastic Agents; Structure-Activity Relationship; Neoplasms; Animals; Drug Repositioning
PubMed: 38803122
DOI: 10.1080/17460441.2024.2355329 -
Chemico-biological Interactions May 2024Head and neck squamous cell carcinoma (HNSCC) faces low response rates to anti-PD-1 immunotherapies, highlighting the need for enhanced treatment strategies. Auranofin,...
Head and neck squamous cell carcinoma (HNSCC) faces low response rates to anti-PD-1 immunotherapies, highlighting the need for enhanced treatment strategies. Auranofin, which inhibits thioredoxin reductase (TrxR) through its gold-based composition, has shown potential in cancer treatment. It targets the TrxR system, essential for safeguarding cells from oxidative stress. The overproduction of TrxR in cancerous cells supports their proliferation. However, auranofin's interference with this system can upset the cellular redox equilibrium, boost levels of reactive oxygen species, and trigger the death of cancer cells. This study is the first to highlight TXNRD1 as a crucial factor contributing to resistance to anti-PD-1 treatment in HNSCC. In this study, we identified targetable regulators of resistance to immunotherapy-induced ferroptosis in HNSCC. We observed a link of thioredoxin reductase 1 (TXNRD1) with tumoral PD-L1 expression and ferroptosis suppression in HNSCC. Moreover, HNSCC tumors with aberrant TXNRD1 expression exhibited a lack of PD-1 response, NRF2 overexpression, and PD-L1 upregulation. TXNRD1 inhibition promoted ferroptosis in HNSCC cells with NRF2 activation and in organoid tumors derived from patients lacking a PD-1 response. Mechanistically, TXNRD1 regulated PD-L1 transcription and maintained the redox balance by binding to ribonucleotide reductase regulatory subunit M2 (RRM2). TXNRD1 expression disruption sensitized HNSCC cells to anti-PD-1-mediated Jurkat T-cell activation, promoting tumor killing through ferroptosis. Moreover, TXNRD1 inhibition through auranofin cotreatment synergized with anti-PD-1 therapy to potentiate immunotherapy-mediated ferroptosis by mediating CD8 T-cell infiltration and downregulating PD-L1 expression. Our findings indicate that targeting TXNRD1 is a promising therapeutic strategy for improving immunotherapy outcomes in patients with HNSCC.
Topics: Humans; Thioredoxin Reductase 1; Head and Neck Neoplasms; Ferroptosis; Auranofin; B7-H1 Antigen; Cell Line, Tumor; Animals; Squamous Cell Carcinoma of Head and Neck; Mice; Programmed Cell Death 1 Receptor; Immune Checkpoint Inhibitors; NF-E2-Related Factor 2; Reactive Oxygen Species
PubMed: 38636790
DOI: 10.1016/j.cbi.2024.111004 -
Brain Research Jul 2024Alzherimer's disease (AD) is an age-dependent ubiquitous ailment worldwide with limited therapies that only alleviate the symptoms of AD but do not cure them entirely...
Alzherimer's disease (AD) is an age-dependent ubiquitous ailment worldwide with limited therapies that only alleviate the symptoms of AD but do not cure them entirely because of the restricted blood-brain barrier passage of the drug. Hence with new advanced technology, nanoparticles can offer an opportunity as the active candidate to overcome the above limitations. Aurothioglucose, a synthetic glucose derivative of the gold compound, has been clinically proven to be an effective anti-inflammatory drug for rheumatic arthritis. Recently, several scientific groups have developed gold nanoparticle preparations and tested them for the treatment of dementia. This study was planned to prepare the PLGA nanoparticles of aurothioglucose (ATG) and check the neuroprotective potential against STZ-induced AD in rats. The nanoparticles were prepared using the double emulsion solvent evaporation method and characterized for various parameters such as drug-excipient interaction, particle size, zeta potential, and morphology. Then, rats were injected STZ (3 mg/kg/i.c.v., days 1 and 3) and ATG (5 and 10 mg/kg/s.c.), ATG NPs (2.5 and 5 mg/kg/s.c.) and donepezil (2 mg/kg/p.o) from 15th to 29th day. Behavior parameters were performed using an actophotometer, MWM, and ORT. On the 30th day, all the animals were sacrificed, and the brains were isolated for estimating biochemical, neurochemical, and proinflammatory markers. It was observed that ATG NPs significantly restored all behavior and neurotransmitter alterations caused by STZ. Also, it increased antioxidant levels and decreased inflammatory cytokines significantly, then ATG alone. Thus, the study suggests that ATG loaded PLGA NPs could be used as a novel therapeutic strategy to slow the process of AD.
Topics: Animals; Alzheimer Disease; Rats; Neuroprotective Agents; Streptozocin; Male; Nanoparticles; Rats, Wistar; Neuroprotection; Disease Models, Animal; Brain
PubMed: 38570152
DOI: 10.1016/j.brainres.2024.148906 -
Biomedicine & Pharmacotherapy =... May 2024Thioredoxin reductase 1 (TrxR1) has emerged as a promising target for cancer therapy. In our previous research, we discovered several new TrxR1 inhibitors and found that...
Thioredoxin reductase 1 (TrxR1) has emerged as a promising target for cancer therapy. In our previous research, we discovered several new TrxR1 inhibitors and found that they all have excellent anti-tumor activity. At the same time, we found these TrxR1 inhibitors all lead to an increase in AKT phosphorylation in cancer cells, but the detailed role of AKT phosphorylation in TrxR1 inhibitor-mediated cell death remains unclear. In this study, we identified the combination of AKT and TrxR1 inhibitor displayed a strong synergistic effect in colon cancer cells. Furthermore, we demonstrated that the synergistic effect of auranofin (TrxR1 inhibitor) and MK-2206 (AKT inhibitor) was caused by ROS accumulation. Importantly, we found that ATM inhibitor KU-55933 can block the increase of AKT phosphorylation caused by auranofin, and exhibited a synergistic effect with auranofin. Taken together, our study demonstrated that the activation of ATM/AKT pathway is a compensatory mechanism to cope with ROS accumulation induced by TrxR1 inhibitor, and synergistic targeting of TrxR1 and ATM/AKT pathway is a promising strategy for treating colon cancer.
Topics: Humans; Colonic Neoplasms; Proto-Oncogene Proteins c-akt; Thioredoxin Reductase 1; Drug Synergism; Auranofin; Ataxia Telangiectasia Mutated Proteins; Reactive Oxygen Species; Signal Transduction; Heterocyclic Compounds, 3-Ring; Cell Line, Tumor; Phosphorylation; Morpholines; HCT116 Cells; Pyrones
PubMed: 38565059
DOI: 10.1016/j.biopha.2024.116507 -
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 -
ACS Applied Bio Materials Mar 2024Triple-negative breast cancer (TNBC) remains a clinical challenge due to molecular, metabolic, and genetic heterogeneity as well as the lack of validated drug targets....
Triple-negative breast cancer (TNBC) remains a clinical challenge due to molecular, metabolic, and genetic heterogeneity as well as the lack of validated drug targets. Thus, therapies or delivery paradigms are needed. Gold-derived compounds including the FDA-approved drug, auranofin have shown promise as effective anticancer agents against several tumors. To improve the solubility and bioavailability of auranofin, we hypothesized that the nanodelivery of auranofin using biodegradable chitosan modified polyethylene glycol (PEG) nanoparticles (NPs) will enhance anticancer activity against TNBC by comparing the best nanoformulation with the free drug. The selection of the nanoformulation was based on synthesis of various chitosan PEG copolymers via formaldehyde-mediated engraftment of PEG onto chitosan to form [chitosan--PEG] copolymer. Furthermore, altered physiochemical properties of the copolymer was based on the formaldehyde ratio towards nanoparticles (CP 1-4 NPs). Following the recruitment of PEG onto the chitosan polymer surface, we explored how this process influenced the stiffness of the nanoparticle using atomic force microscopy (AFM), a factor crucial for in vitro and in vivo studies. Our objective was to ensure the full functionality and inherent properties of chitosan as the parent polymer was maintained without allowing PEG to overshadow chitosan's unique cationic properties while improving solubility in neutral pH. Hence, CP 2 NP was chosen. To demonstrate the efficacy of CP 2 NP as a good delivery carrier for auranofin, we administered a dose of 3 mg/kg of auranofin, in contrast to free auranofin, which was given at 5 mg/kg. In vivo studies revealed the potency of encapsulated auranofin against TNBC cells with a severe necrotic effect following treatment superior to that of free auranofin. In conclusion, chitosan--PEG nanoparticles have the potential to be an excellent delivery system for auranofin, increasing its effectiveness and potentially reducing its clinical limitations.
Topics: Humans; Chitosan; Triple Negative Breast Neoplasms; Auranofin; Polymers; Polyethylene Glycols; Nanoparticles; Formaldehyde
PubMed: 38450675
DOI: 10.1021/acsabm.4c00184 -
Anticancer Research Mar 2024Osteosarcoma (OS) is a rare malignant tumor with a poor survival rate. Our previous study reported that auranofin (AUR), a thioredoxin reductase inhibitor, suppresses OS...
BACKGROUND/AIM
Osteosarcoma (OS) is a rare malignant tumor with a poor survival rate. Our previous study reported that auranofin (AUR), a thioredoxin reductase inhibitor, suppresses OS pulmonary metastases; however, the local progression of OS is not affected, in vivo. Nonetheless, the development of augmentation therapy with AUR to inhibit OS local progression remains challenging. Celecoxib (CE), an anti-inflammatory drug, potently enhances the therapeutic activity of AUR against colon cancer. Consequently, this study investigated the combined effects of AUR and CE on OS local progression and pulmonary metastases, in vivo.
MATERIALS AND METHODS
C3H/HeSlc mice were implanted with the murine OS cell line, LM8. The mice were treated either with a vehicle control, AUR, or combination of AUR and CE (AUR-CE). The primary tumor size and weight were evaluated for the study duration and at resection, respectively. Hematoxylin and eosin and Ki-67 staining were performed to evaluate OS local progression and pulmonary metastases.
RESULTS
Mice in the AUR-CE group showed statistically significantly suppressed tumor sizes and weights at the time of excision compared with those in the vehicle. The mice in the AUR group did not show a statistically significant effect. Histopathological analysis of the primary tumor revealed a statistically significant decrease of the Ki-67-positive cells in the AUR-CE group compared with the vehicle group. Histopathological and quantitative analyses demonstrated that the AUR and AUR-CE groups had statistically significant reductions in the development of OS pulmonary metastases compared with the vehicle group.
CONCLUSION
The combination of AUR and CE significantly inhibited OS local progression and pulmonary metastases.
Topics: Animals; Mice; Auranofin; Celecoxib; Ki-67 Antigen; Mice, Inbred C3H; Osteosarcoma; Lung Neoplasms; Cell Line, Tumor; Bone Neoplasms
PubMed: 38423669
DOI: 10.21873/anticanres.16899 -
Cancer Genomics & Proteomics 2024Chemoresistance in rhabdomyosarcoma (RMS) is associated with poor survival, necessitating the development of novel anticancer drugs. Auranofin (AUR), an anti-rheumatic...
BACKGROUND/AIM
Chemoresistance in rhabdomyosarcoma (RMS) is associated with poor survival, necessitating the development of novel anticancer drugs. Auranofin (AUR), an anti-rheumatic drug, is a thioredoxin reductase (TXNRD) inhibitor with anticancer properties. Although patient-derived xenograft (PDX) models are essential for studying cancer biology, reports on sarcomas using the PDX model are scarce because of their rarity. This study aimed to investigate the effectiveness of AUR treatment in RMS using a PDX model to evaluate its impact on local progression.
MATERIALS AND METHODS
A 20-year-old woman who was diagnosed with alveolar RMS was used to generate the PDX model. RMS PDX tumors were implanted in nude mice and divided into non-treated (vehicle) and treated (AUR) groups. Tumor volume and weight were evaluated, and immunohistochemical staining was performed to evaluate local progression of the sarcoma. The relationship between the TXNRD-1 expression and survival probability of patients with RMS was evaluated using publicly available expression cohorts.
RESULTS
AUR significantly suppressed RMS tumor progression over time. It also significantly suppressed the tumor size and weight at the time of excision. Histological evaluation showed that AUR induced oxidative stress in the PDX mouse models and inhibited the local progression of RMS by inducing apoptosis. High TXNRD-1 expression was found to be a negative prognostic factor for overall survival in patients with RMS.
CONCLUSION
AUR-induced inhibition of TXNRDs can significantly impede the local progression of RMS through the oxidative stress-apoptosis pathway as demonstrated in PDX models. Thus, targeting TXNRD inhibition may be a promising therapeutic strategy for the treatment of RMS.
Topics: Female; Humans; Animals; Mice; Young Adult; Adult; Thioredoxin-Disulfide Reductase; Mice, Nude; Rhabdomyosarcoma; Sarcoma; Auranofin; Disease Models, Animal; Xenograft Model Antitumor Assays; Cell Line, Tumor
PubMed: 38423598
DOI: 10.21873/cgp.20439