The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1

Redox Biology, Год журнала: 2023, Номер 62, С. 102703 - 102703

Опубликована: Апрель 17, 2023

Ferroptosis is defined as cell death triggered by iron-dependent lipid peroxidation that preventable antioxidant compounds such ferrostatin-1. Endogenous suppressors of ferroptosis include FSP-1 and the selenoprotein GPX4, latter which directly enzymatically reduces hydroperoxides. Small molecules trigger RSL3, ML162, ML210; these are often used in studies generally considered GPX4 inhibitors. Here, we found RSL3 ML162 completely lack capacity inhibiting enzymatic activity recombinant GPX4. Surprisingly, were instead to be efficient inhibitors another selenoprotein, TXNRD1. Other known TXNRD1, including auranofin, TRi-1 TRi-2, also inducers but could not suppressed with Our results collectively suggest prior using may need reevaluated context regards additional enzyme targets mechanisms action involved.

Язык: Английский

---

Dual inhibition of thioredoxin reductase and proteasome is required for auranofin-induced paraptosis in breast cancer cells

Cell Death and Disease, Год журнала: 2023, Номер 14(1)

Опубликована: Янв. 19, 2023

Abstract Auranofin (AF), a gold (I)-containing phosphine compound, is being investigated for oncological application as repurposed drug. We show here that 4~5 µM AF induces paraptosis, non-apoptotic cell death mode characterized by dilation of the endoplasmic reticulum (ER) and mitochondria, in breast cancer cells. Although covalent inhibition thioredoxin reductase (TrxR), an enzyme critically controls intracellular redox homeostasis, considered primary mechanism AF’s anticancer activity, knockdown TrxR1 did not induce paraptosis. Instead, both plus proteasome inhibitor (PI), bortezomib (Bz), 2 μM Bz induced thereby mimicking effect 5 AF. These results suggest paraptosis requires proteasome. found knockdown/Bz or subtoxic doses selectively cells, sparing non-transformed MCF10A whereas killed GSH depletion was to be more critical than ROS generation dual TrxR1/proteasome inhibition. In this process, ATF4/CHAC1 (glutathione-specific gamma-glutamylcyclotransferase 1) axis leads degradation, contributing proteotoxic stress possibly due accumulation misfolded thiol-containing proteins. paraptosis-inducing strategy PI may provide effective therapeutic against pro-apoptotic therapy-resistant cancers reduce potential side effects associated with high-dose

Язык: Английский

---

Molecular mechanisms and clinical implications of the gold drug auranofin

Coordination Chemistry Reviews, Год журнала: 2023, Номер 493, С. 215323 - 215323

Опубликована: Июль 9, 2023

Язык: Английский

---

Exploring Strategies to Prevent and Treat Ovarian Cancer in Terms of Oxidative Stress and Antioxidants

Antioxidants, Год журнала: 2025, Номер 14(1), С. 114 - 114

Опубликована: Янв. 20, 2025

Oxidative stress is a state of imbalance between the production reactive oxygen species (ROS) and nitrogen (RNS) antioxidant defence system in body. may be associated with variety diseases, such as ovarian cancer, diabetes mellitus, neurodegeneration. The generation oxidative one common refractory malignancies among gynaecological tumours, several factors. On hand, increased metabolism cancer cells can lead to ROS, on other impaired not able effectively scavenge excessive ROS. In addition, chemotherapy radiotherapy elevate cells. cause damage, promote development even result drug resistance. Therefore, studying important for prevention treatment cancer. Antioxidants, markers stress, might serve strategies preventing treating this review, we will discuss complex relationship well role therapeutic potential antioxidants thus guiding future research clinical interventions.

Язык: Английский

---

New Insights into the Behavior of NHC-Gold Complexes in Cancer Cells

Pharmaceutics, Год журнала: 2023, Номер 15(2), С. 466 - 466

Опубликована: Янв. 31, 2023

Among the non-platinum antitumor agents, gold complexes have received increased attention owing to their strong antiproliferative effects, which generally occur through non-cisplatin-like mechanisms of action. Several studies revealed that many cytotoxic compounds, such as N-heterocyclic carbene (NHC)-gold(I) complexes, are potent thioredoxin reductase (TrxR) inhibitors. Many other pathways been supposed be altered by coordination protein targets. Within this frame, we selected two gold(I) based on aromatic ligands tested cancer cells. Differently from bis [1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene]gold(I) bromide (Au4BC), [1-methyl-3-acridineimidazolin-2-ylidene]gold(I) tetrafluoroborate (Au3BC) inhibited TrxR1 activity in vitro. Treatment Huh7 hepatocellular carcinoma (HCC) cells, and MDA-MB-231 triple-negative breast (TNBC) with Au4BC cell viability, reactive oxygen species (ROS) levels, caused DNA damage, induced autophagy apoptosis. Notably, found that, although Au3BC activity, no effect viabilities HCC BC cells was observed. At molecular level, a protective response mechanism inducing up-regulation RAD51 p62 expression, proteins involved damage repair autophagy, respectively. gene knock-down sensitivity significant reduction induction apoptosis autophagy. All together, these results suggest NHC-Gold Au4BC, showed different action, either dependent or independent inhibition. As result, were promising candidates anticancer drugs for treatment BC.

Язык: Английский

---

Thioredoxin Domain Containing 5 (TXNDC5): Friend or Foe?

Current Issues in Molecular Biology, Год журнала: 2024, Номер 46(4), С. 3134 - 3163

Опубликована: Апрель 4, 2024

This review focuses on the thioredoxin domain containing 5 (TXNDC5), also known as endoplasmic reticulum protein 46 (ERp46), a member of disulfide isomerase (PDI) family with dual role in multiple diseases. TXNDC5 is highly expressed endothelial cells, fibroblasts, pancreatic β-cells, liver and hypoxic tissues, such cancer cells atherosclerotic plaques. plays crucial regulating cell proliferation, apoptosis, migration, antioxidative stress. Its potential significance warrants further investigation, given altered adaptable metabolism tumor cells. It has been reported that both high low levels expression are associated diseases, arthritis, cancer, diabetes, brain infections, well worse prognoses. attributed to oncogenic tumor-suppressive features. concluded acts foe responds metabolic cellular stress signals promote survival against apoptosis. Conversely, normal friend safeguard oxidative Therefore, could serve viable biomarker or even pharmacological target.

Язык: Английский

---

The molecular mechanism of gemcitabine in inhibiting the HIF-1α/VEGFB/FGF2/FGFR1 signaling pathway for ovarian cancer treatment

Discover Oncology, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 3, 2025

Язык: Английский

---

Auranofin induces disulfide bond-mimicking S-Au adducts in protein thiol pairs

Journal of Biological Chemistry, Год журнала: 2025, Номер 301(3), С. 108159 - 108159

Опубликована: Янв. 4, 2025

Язык: Английский

---

Methods to Evaluate Changes in Mitochondrial Structure and Function in Cancer

Cancers, Год журнала: 2023, Номер 15(9), С. 2564 - 2564

Опубликована: Апрель 29, 2023

Mitochondria are regulators of key cellular processes, including energy production and redox homeostasis. Mitochondrial dysfunction is associated with various human diseases, cancer. Importantly, both structural functional changes can alter mitochondrial function. Morphologic quantifiable in mitochondria affect their function contribute to disease. Structural include alterations cristae morphology, DNA integrity quantity, dynamics, such as fission fusion. Functional parameters related biology the reactive oxygen species, bioenergetic capacity, calcium retention, membrane potential. Although these occur independently one another, structure often interrelated. Thus, evaluating crucial understanding molecular events involved disease onset progression. This review focuses on relationship between cancer, a particular emphasis gynecologic malignancies. Selecting methods tractable may be critical identifying targeting mitochondria-related therapeutic options. Methods measure function, benefits limitations, summarized.

Язык: Английский

---

Bioconjugation of the gold drug auranofin to human ferritin yields a potent cytotoxin

Journal of Drug Delivery Science and Technology, Год журнала: 2023, Номер 87, С. 104822 - 104822

Опубликована: Авг. 4, 2023

Ferritin may serve as a nanocarrier for the selective delivery of anticancer metallodrugs. Here, we have prepared and characterized well-defined conjugate between gold drug auranofin apoferritin containing ∼14 atoms per nanocage ([email protected] hereafter). Site directed mutagenesis combined with ESI MS ICP-OES experiments revealed that binding occurs exclusively at cysteines 90 102. [email was found to manifest potent cytotoxic properties against A2780 cancer cells overcome cisplatin resistance. Interestingly, observed induced alterations in NMR-detectable metabolome very similar those caused by AF implying roughly identical mode action. Accordingly, also show like metalates efficiently C-terminal dodecapeptide thioredoxin reductase bearing thiol-selenol active site (this enzyme being main intracellular target AF). Some features cellular uptake subsequent release are analyzed. On these grounds, is proposed an innovative agent, pharmacological profile free AF, where reactivity center, its side effects tightly controlled ferritin nanocage.

Язык: Английский

---