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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 -
BioRxiv : the Preprint Server For... Jun 2024Lysine Specific Demethylase 1 (KDM1A / LSD1) regulates mitochondrial respiration and stabilizes HIF-1A (hypoxia-inducible factor 1A). HIF-1A modulates reactive oxygen...
Lysine Specific Demethylase 1 (KDM1A / LSD1) regulates mitochondrial respiration and stabilizes HIF-1A (hypoxia-inducible factor 1A). HIF-1A modulates reactive oxygen species (ROS) levels by increasing cellular glucose uptake, glycolysis, and endogenous antioxidants. The role of KDM1A in cellular ROS response has not previously been described. We determined the role of KDM1A in regulating the ROS response and the utility of KDM1A inhibitors in combination with ROS-inducing cancer therapies. Our results show that KDM1A inhibition sensitized cells to oxidative stress and increased total cellular ROS, which was mitigated by treatment with the antioxidant N-acetyl cysteine. KDM1A inhibition decreased basal mitochondrial respiration and impaired induction of HIF-1A after ROS exposure. Overexpression of HIF-1A salvaged cells from KDM1A inhibition enhanced sensitivity to ROS. Thus we found that increased sensitivity of ROS after KDM1A inhibition was mediated by HIF-1A and depletion of endogenous glutathione. We also show that KDM1A-specific inhibitor bizine synergized with antioxidant-depleting therapies, buthionine sulfoximine, and auranofin in rhabdomyosarcoma cell lines (Rh28 and Rh30). In this study, we describe a novel role for KDM1A in regulating HIF- 1A functions under oxidative stress and found that dual targeting of KDM1A and antioxidant systems may serve as an effective combination anticancer strategy.
PubMed: 38915482
DOI: 10.1101/2024.06.12.597953 -
Neoplasia (New York, N.Y.) Jul 2024Thioredoxin reductases are frequently overexpressed in various solid tumors as a protective mechanism against heightened oxidative stress. Inhibitors of this system,...
Thioredoxin reductases are frequently overexpressed in various solid tumors as a protective mechanism against heightened oxidative stress. Inhibitors of this system, such as Auranofin, are effective in eradicating cancer cells. However, the clinical significance of thioredoxin reductase 1 (TrxR1) in lung cancer, as well as the potential for its antagonist as a treatment option, necessitated further experimental validation. In this study, we observed significant upregulation of TrxR1 specifically in non-small cell lung cancer (NSCLC), rather than small cell lung cancer. Moreover, TrxR1 expression exhibited associations with survival rate, tumor volume, and histological classification. We developed a novel TrxR1 inhibitor named LW-216 and assessed its antitumor efficacy in NSCLC. Our results revealed that LW-216 is effectively bound with intracellular TrxR1 at sites R371 and G442, facilitating TrxR1 ubiquitination and suppressing TrxR1 expression, while not affecting TrxR2 expression. Treatment of LW-216-induced DNA damage and cell apoptosis in NSCLC cells through the generation of reactive oxygen species (ROS). Importantly, supplementation with N-acetylcysteine (NAC) or ectopic TrxR1 expression reversed LW-216-induced apoptosis. Furthermore, LW-216 displayed potent tumor growth inhibition in NSCLC cell-implanted mice, reducing TrxR1 expression in xenografts. Remarkably, LW-216 exhibited superior antitumor activity compared to Auranofin in vivo. Collectively, our research provides compelling evidence supporting the potential of targeting TrxR1 by LW-216 as a promising therapeutic strategy for NSCLC.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Thioredoxin Reductase 1; Reactive Oxygen Species; Lung Neoplasms; Apoptosis; Animals; Mice; Ubiquitination; Xenograft Model Antitumor Assays; Cell Line, Tumor; Proteolysis; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Disease Models, Animal; Male; Antineoplastic Agents
PubMed: 38733769
DOI: 10.1016/j.neo.2024.101004 -
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 -
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 -
BioRxiv : the Preprint Server For... Apr 2024Ferroptosis is an iron-dependent, non-apoptotic form of cell death resulting from the accumulation of lipid peroxides. Colorectal cancer (CRC) accumulates high levels of...
Ferroptosis is an iron-dependent, non-apoptotic form of cell death resulting from the accumulation of lipid peroxides. Colorectal cancer (CRC) accumulates high levels of intracellular iron and reactive oxygen species (ROS), thereby sensitizing cells to ferroptosis. The selenoprotein glutathione peroxidase (GPx4) is a key enzyme in the detoxification of lipid peroxides and can be inhibited by the compound (S)-RSL3 ([1S,3R]-RSL3). However, the stereoisomer (R)-RSL3 ([1R,3R]-RSL3), which does not inhibit GPx4, exhibits equipotent activity to (S)-RSL3 across a panel of CRC cell lines. Utilizing CRC cell lines with an inducible knockdown of GPx4, we demonstrate that (S)-RSL3 sensitivity does not align with GPx4 dependency. Subsequently, a biotinylated (S)-RSL3 was then synthesized to perform affinity purification-mass spectrometry (AP-MS), revealing that (S)-RSL3 acts as a pan-inhibitor of the selenoproteome, targeting both the glutathione and thioredoxin peroxidase systems as well as multiple additional selenoproteins. To investigate the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC, we employed further chemical and genetic approaches to disrupt selenoprotein function. The findings demonstrate that the selenoprotein inhibitor Auranofin can induce ferroptosis and/or oxidative cell death both and . Consistent with this data we observe that AlkBH8, a tRNA-selenocysteine methyltransferase required for the translational incorporation of selenocysteine, is essential for CRC growth. In summary, our research elucidates the complex mechanisms underlying ferroptosis in CRC and reveals that modulation of the selenoproteome provides multiple new therapeutic targets and opportunities in CRC.
PubMed: 38617233
DOI: 10.1101/2024.03.29.587381 -
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 -
EJNMMI Radiopharmacy and Chemistry Nov 2023Heterometallic gold metallacages are of great interest for the incorporation of several cations. Especially in nuclear medicine, those metallacages can serve as a...
BACKGROUND
Heterometallic gold metallacages are of great interest for the incorporation of several cations. Especially in nuclear medicine, those metallacages can serve as a platform for radionuclides relevant for imaging or therapy (e.g. Ga or Lu). Moreover, the radionuclide Au is an attractive beta emitter, for potential application in nuclear medicine. Here, we aim to synthesize a new set of gold metallacages and to study their ability to coordinate to Ga, Lu and Au.
RESULTS
New heterometallic gold metallacages of composition [M{Au(L-κS)}] (M = La, Tb, Lu or Y) and [Ga{Au(L-κS)}]NO have been synthesized from 2,6-dipicolinoylbis(N,N-morpholinylthiourea) (HL) with [AuCl(THT)] and the target M metal ions in yields ranging from 33 (Lu) to 62% (Tb). The characterization of the compounds bases on ESI-MS, H NMR, IR, EA and single-crystal X-ray diffraction techniques (all except the Ga derivative). Selected gold cages derived from HL were compared to previously reported gold cages that were derived from 2,6-dipicolinoylbis(N,N-diethylthiourea) (HL). The tested metallacages show similar IC values close to that of auranofin in four different cancer cell lines (MCF-7, PC-3, U383, U343), e.g. 4.5 ± 0.7 µM for [Ga{Au(L)}]NO on PC-3. The radiolabeling experiments thereof show high radiochemical purities with Ga and Au and low radiochemical purity with Lu.
CONCLUSIONS
The results indicate that these gold metallacages could serve as a novel platform for inclusion of different (radio)nuclides with potential theranostic applications in nuclear medicine.
PubMed: 37982944
DOI: 10.1186/s41181-023-00225-z