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Biochemical Pharmacology Dec 2023Targeting overexpressed thioredoxin reductase (TrxR) in cancer cells to induce oxidative stress has been proved to be an effective strategy for cancer therapy. However,...
Targeting overexpressed thioredoxin reductase (TrxR) in cancer cells to induce oxidative stress has been proved to be an effective strategy for cancer therapy. However, the treatment was hindered by the low efficiency and frequent administration of TrxR inhibitors, and hence more potent TrxR inhibitors were urgently needed. Herein, we designed and synthesized a series of TrxR inhibitors based on arsenicals. Among these, compound 1d inhibited the proliferation of a variety of cancer cells at low micromolar concentrations and exhibited low toxicity to normal cells. Importantly, compound 1d induced the accumulation of reactive oxygen species (ROS) by inhibiting the TrxR activity, further causing the collapse of the redox system, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and DNA damage, followed by oxidative stress-induced cell apoptosis. In vivo data showed that, compared with the clinical TrxR inhibitor auranofin (AUR), compound 1d could more effectively eliminate tumors by 90 % at a dose of 1.5 mg/kg without any obvious side effects. These results indicated that compound 1d was a potent TrxR inhibitor against cancer.
Topics: Humans; Thioredoxin-Disulfide Reductase; Oxidative Stress; Reactive Oxygen Species; Antioxidants; Auranofin; Neoplasms; Enzyme Inhibitors; Apoptosis
PubMed: 37931662
DOI: 10.1016/j.bcp.2023.115908 -
Cancers Oct 2023High-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer cases, and the survival rate remains remarkably low due to the lack of effective long-term...
High-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer cases, and the survival rate remains remarkably low due to the lack of effective long-term consolidation therapies. Clinical remission can be temporarily induced by platinum-based chemotherapy, but death subsequently results from the extensive growth of a platinum-resistant component of the tumor. This work explores a novel treatment against HGSOC using the gold complex auranofin (AF). AF primarily functions as a pro-oxidant by inhibiting thioredoxin reductase (TrxR), an antioxidant enzyme overexpressed in ovarian cancer. We investigated the effect of AF on TrxR activity and the various mechanisms of cytotoxicity using HGSOC cells that are clinically sensitive or resistant to platinum. In addition, we studied the interaction between AF and another pro-oxidant, L-buthionine sulfoximine (L-BSO), an anti-glutathione (GSH) compound. We demonstrated that AF potently inhibited TrxR activity and reduced the vitality and viability of HGSOC cells regardless of their sensitivities to platinum. We showed that AF induces the accumulation of reactive oxygen species (ROS), triggers the depolarization of the mitochondrial membrane, and kills HGSOC cells by inducing apoptosis. Notably, AF-induced cell death was abrogated by the ROS-scavenger N-acetyl cysteine (NAC). In addition, the lethality of AF was associated with the activation of caspases-3/7 and the generation of DNA damage, effects that were also prevented by the presence of NAC. Finally, when AF and L-BSO were combined, we observed synergistic lethality against HGSOC cells, which was mediated by a further increase in ROS and a decrease in the levels of the antioxidant GSH. In summary, our results support the concept that AF can be used alone or in combination with L-BSO to kill HGSOC cells regardless of their sensitivity to platinum, suggesting that the depletion of antioxidants is an efficient strategy to mitigate the course of this disease.
PubMed: 37958311
DOI: 10.3390/cancers15215136 -
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 -
3 Biotech Dec 2023Globally, Leishmaniasis affects underprivileged communities of the nations and chemotherapy remains one of the preferred treatment options. However, the cytotoxicity,...
UNLABELLED
Globally, Leishmaniasis affects underprivileged communities of the nations and chemotherapy remains one of the preferred treatment options. However, the cytotoxicity, side effects, and cost of the present chemotherapies limit their utilization. Auranofin [an organogold compound having significant structural similarity with triethyl-phosphine (TEP)] has been reported as an effective therapy for Leishmaniasis treatment. Considering the high cost of gold and the strong affinity of cerium oxide nanoparticles (CeNPs) to phosphine ligands, we designed TEP-decorated CeNPs (CeNPs-TEP) and used them as a novel antileishmanial agent. The hydrodynamic size of synthesized CeNPs and CeNPs-TEP was observed to be 22.2 ± 3.7 nm and 92.11 ± 6.2 nm, respectively. CeNPs-TEP provided aqueous stability to TEP as TEP alone is extremely unstable in water. Exposure of CeNPs-TEP showed ~ 60 and ~ 82% cell death in Ag83 promastigotes after 24 and 48 h, respectively. The same concentration of CeNPs-TEP did not affect the cellular viability of RAW 264.7 macrophage cells significantly. The oxidative stress and depolarization of the mitochondrial membrane were also observed after the treatment of CeNPs-TEP. Exposure of CeNPs-TEP induced a ~ 2.2-fold increase in ROS generation inside Ag83 cells. Dual staining with ethidium bromide and acridine orange reveals that these processes ultimately result in cell death. The results conclude that a combination of CeNPs and TEP could open the door for developing novel antileishmanial therapeutics in the future.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s13205-023-03813-7.
PubMed: 38009165
DOI: 10.1007/s13205-023-03813-7 -
Biometals : An International Journal on... Oct 2023Auranofin ([1-(thio-κS)-β-D-glucopyranose-2,3,4,6-tetraacetato](triethylphosphine)-gold) is a leading gold-based drug clinically used to treat arthritis. In the last...
Auranofin ([1-(thio-κS)-β-D-glucopyranose-2,3,4,6-tetraacetato](triethylphosphine)-gold) is a leading gold-based drug clinically used to treat arthritis. In the last years, it entered various drug reprofiling programs, and it has been found promising against various forms of tumor, including ovarian cancer. Evidence showed as its antiproliferative profile mainly depends on the inhibition of thioredoxin reductase (TrxR), being this mitochondrial system its main target. In this context, we report here the synthesis and biological evaluation of a novel complex designed as auranofin analogue obtained through the conjugation of a phenylindolylglyoxylamide ligand (which belongs to the so-called PIGA TSPO ligand family) with the auranofin-derived cationic fragment [Au(PEt)]. This complex is characterized by two parts. The phenylindolylglyoxylamide moiety, owing to its high affinity for TSPO (in the low nM range) should drive the compound to target mitochondria, whereas the [Au(PEt)] cation is the actual anticancer-active molecular fragment. Overall, we wanted to offer the proof-of-concept that by coupling PIGA ligands to anticancer gold active moieties, it is possible to preserve and even improve anticancer effects, opening the avenue to a reliable approach for targeted therapy.
Topics: Humans; Female; Auranofin; Pharmacophore; Ligands; Antineoplastic Agents; Gold; Thioredoxin-Disulfide Reductase; Ovarian Neoplasms; Cell Line, Tumor; Receptors, GABA
PubMed: 36869967
DOI: 10.1007/s10534-023-00496-8 -
Physical Chemistry Chemical Physics :... Feb 2024Oxidative addition of the S-Se bond to Au(I) complexes is discussed for a series of 26 auranofin (AF) derivatives. AF and its analogues are Au(I) complexes with...
Oxidative addition of the S-Se bond to Au(I) complexes is discussed for a series of 26 auranofin (AF) derivatives. AF and its analogues are Au(I) complexes with recognized anticancer activity that act by binding and inhibiting the thioredoxin reductase (TrxR) enzyme. Generally, the oxidative addition to Au(I) is a sluggish reaction under mild conditions (, a high activation barrier - Δ), which is also verified here for AF, Δ = 33.0 kcal mol. However, we predicted that subtle changes in the AF ligands can make the process feasible under standard conditions. For instance, the exchange of -PEt by -P(Et)(OEt), which is a weaker electron σ-donor, reduced the activation barrier to 17.1 kcal mol. Furthermore, substitution of the -SAtg ligand by -Cl leads to a Δ value of 22.5 kcal mol. Overall, the reaction is driven by the nucleophilic attack of the S-Se bond on the Au(I) center, attributed mainly to the charge transfer (4p) → (6p), which characterizes the addition step. At the transition state (TS) point, the (5d) → σ*(S-Se) charge transfer becomes relevant, facilitating the S-Se bond breakage and the oxidation step. In addition to the electron transfers, the strain energy to deform the linear Au(I) geometry to the tetracoordinated Au(III) arrangement in the TS structure plays a primary role in explaining the trends in the activation barriers. Finally, the activation barrier (Δ) and reaction energy (Δ°) were correlated for most of the complexes studied, which suggests that the reaction passes through a late or product-like TS and, therefore, the steric and electronic factors affecting Δ also act on Δ°. Overall, the results presented here might open up a new field of investigation for interactions between AF derivatives and TrxR, which contributes to a full understanding of the biological mechanism of action of these species.
PubMed: 38284132
DOI: 10.1039/d3cp04913b -
Biomolecules Jan 2024Atrial calcium transient (CaT) alternans is defined as beat-to-beat alternations in CaT amplitude and is causally linked to atrial fibrillation (AF). Mitochondria play a...
Atrial calcium transient (CaT) alternans is defined as beat-to-beat alternations in CaT amplitude and is causally linked to atrial fibrillation (AF). Mitochondria play a significant role in cardiac excitation-contraction coupling and Ca signaling through redox environment regulation. In isolated rabbit atrial myocytes, ROS production is enhanced during CaT alternans, measured by fluorescence microscopy. Exogenous ROS (tert-butyl hydroperoxide) enhanced CaT alternans, whereas ROS scavengers (dithiothreitol, MnTBAP, quercetin, tempol) alleviated CaT alternans. While the inhibition of cellular NADPH oxidases had no effect on CaT alternans, interference with mitochondrial ROS (ROS) production had profound effects: (1) the superoxide dismutase mimetic MitoTempo diminished CaT alternans and shifted the pacing threshold to higher frequencies; (2) the inhibition of cyt peroxidase by SS-31, and inhibitors of ROS production by complexes of the electron transport chain S1QEL1.1 and S3QEL2, decreased the severity of CaT alternans; however (3) the impairment of mitochondrial antioxidant defense by the inhibition of nicotinamide nucleotide transhydrogenase with NBD-Cl and thioredoxin reductase-2 with auranofin enhanced CaT alternans. Our results suggest that intact mitochondrial antioxidant defense provides crucial protection against pro-arrhythmic CaT alternans. Thus, modulating the mitochondrial redox state represents a potential therapeutic approach for alternans-associated arrhythmias, including AF.
Topics: Animals; Rabbits; Calcium; Reactive Oxygen Species; Antioxidants; Action Potentials; Myocytes, Cardiac; Atrial Fibrillation; Mitochondria; 4-Chloro-7-nitrobenzofurazan
PubMed: 38397381
DOI: 10.3390/biom14020144 -
Research (Washington, D.C.) 2024Achieving antitumor immunotherapy based on hybridization of multiple types of inactivated cells has attracted a lot of attention. However, the hybridized cells of...
Achieving antitumor immunotherapy based on hybridization of multiple types of inactivated cells has attracted a lot of attention. However, the hybridized cells of disordered structure could result in the shedding of antigens and their transfer to immune cells, which suppresses tumor immunity through trogocytosis. Here, we report a strategy for in situ solidification of tumor whole cell by biomineralization for sustained stimulation of antitumor immunity. The near-infrared light was used to accelerate the breaking of Au=P bonds in auranofin, and the exposed Au atoms biomineralize at the secondary structure (β-corner) of the protein to form Au nanocrystals with in situ protein coronas in tumor cells. Au nanocrystals are anchored to the tumor cells through protein coronas, which fixes the morphology and antigens of whole tumor cells, rendering them physiologically inactive. Interestingly, this solidified tumor cell prevents immune cells from undergoing trogocytosis, which inhibits proximal and distal tumor growth. Thus, this study presents the strategy of solidified cells and its potential application in tumor immunotherapy.
PubMed: 38384327
DOI: 10.34133/research.0318 -
Scientific Reports Sep 2023Clostridioides difficile infections (CDIs) are responsible for a significant number of antibiotic-associated diarrheal cases. The standard-of-care antibiotics for C....
Clostridioides difficile infections (CDIs) are responsible for a significant number of antibiotic-associated diarrheal cases. The standard-of-care antibiotics for C. difficile are limited to fidaxomicin and vancomycin, with the recently obsolete metronidazole recommended if both are unavailable. No new antimicrobials have been approved for CDI since fidaxomicin in 2011, despite varying rates of treatment failure among all standard-of-care drugs. Drug repurposing is a rational strategy to generate new antimicrobials out of existing therapeutics approved for other indications. Auranofin is a gold-containing anti-rheumatic drug with antimicrobial activity against C. difficile and other microbes. In a previous report, our group hypothesized that inhibition of selenoprotein biosynthesis was auranofin's primary mechanism of action against C. difficile. However, in this study, we discovered that C. difficile mutants lacking selenoproteins are still just as sensitive to auranofin as their respective wild-type strains. Moreover, we found that selenite supplementation dampens the activity of auranofin against C. difficile regardless of the presence of selenoproteins, suggesting that selenite's neutralization of auranofin is not because of compensation for a chemically induced selenium deficiency. Our results clarify the findings of our original study and may aid drug repurposing efforts in discovering the compound's true mechanism of action against C. difficile.
Topics: Auranofin; Clostridioides; Clostridioides difficile; Fidaxomicin; Selenious Acid; Selenoproteins
PubMed: 37679389
DOI: 10.1038/s41598-023-36796-9 -
ACS Pharmacology & Translational Science Dec 2023Antibody-drug conjugates (ADCs) combine the selectivity of monoclonal antibodies (mAbs) with the efficacy of chemotherapeutics to target cancers without toxicity to...
Shifting the Antibody-Drug Conjugate Paradigm: A Trastuzumab-Gold-Based Conjugate Demonstrates High Efficacy against Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Mouse Model.
Antibody-drug conjugates (ADCs) combine the selectivity of monoclonal antibodies (mAbs) with the efficacy of chemotherapeutics to target cancers without toxicity to normal tissue. Clinically, most chemotherapeutic ADCs are based on complex organic molecules, while the conjugation of metallodrugs to mAbs has been overlooked, despite the resurgent interest in metal-based drugs as cancer chemotherapeutics. In 2019, we described the first gold ADCs containing gold-triphenylphosphane fragments as a proof of concept. The ADCs (based on the antibody trastuzumab) were selective and highly active against HER2-positive breast cancer cells. In this study, we developed site-specific ADCs ( and ) using the cysteine-engineered trastuzumab derivative THIOMAB antibody technology with gold(I)-containing phosphanes and a maleimide-based linker amenable to bioconjugation ( and ). In addition, we developed lysine-directed ADCs with gold payloads based on phosphanes and -heterocyclic carbenes featuring an activated ester moiety ( and ) with trastuzumab ( and ) and another anti-HER2 antibody, pertuzumab ( and ). Both sets of ADCs demonstrated significant anticancer potency in vitro assays. Based on these results, one ADC (), containing the [Au(PEt)] fragment present in FDA-approved auranofin, was selected for an in vivo antitumor efficacy study. Immunocompromised mice xenografted with the HER2-positive human cancer cell line SKBR-3 exhibited almost complete tumor reduction and low toxicity with intravenous administration of . With this highly selective targeting system, we demonstrated that a subnanomolar cytotoxicity profile in cells is not required for an impressive antitumor effect in a mouse xenograft model.
PubMed: 38093840
DOI: 10.1021/acsptsci.3c00270