Vitality, viability, long-term clonogenic survival, cytotoxicity, cytostasis and lethality: what do they mean when testing new investigational oncology drugs?

Discover Oncology, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 5, 2024

Abstract In the field of experimental therapeutics for oncology purposes researchers are continuously evaluating toxicity novel treatment approaches against cancer cells. Within this topic research, it is highly critical to define parameters that denote when cells perturbed in their functionality by a new investigational drug. As goal these achieve cellular demise, then what use and do they mean terms assessing such cell death importance. comment article we highlight definition vitality differentiate from viability, further clonogenic survival chronic fashion. Additionally, recommend term cytotoxicity as general descriptor indicating towards cell, but within encourage sub-classify either cytostasis (i.e., does not allow grow kill either), or lethality (when dies response treatment). A more precise should help advance better defining mechanisms action drugs.

Language: Английский

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Auranofin-Loaded Chitosan Nanoparticles Demonstrate Potency against Triple-Negative Breast Cancer

ACS Applied Bio Materials, Journal Year: 2024, Volume and Issue: 7(3), P. 2012 - 2022

Published: March 7, 2024

Triple-negative breast cancer (TNBC) remains a clinical challenge due to molecular, metabolic, and genetic heterogeneity as well the lack of validated drug targets. Thus, therapies or delivery paradigms are needed. Gold-derived compounds including FDA-approved drug, auranofin have shown promise effective anticancer agents against several tumors. To improve solubility bioavailability auranofin, we hypothesized that nanodelivery using biodegradable chitosan modified polyethylene glycol (PEG) nanoparticles (NPs) will enhance activity TNBC by comparing best nanoformulation with free drug. The selection was based on synthesis various PEG copolymers via formaldehyde-mediated engraftment onto form [chitosan-g-PEG] copolymer. Furthermore, altered physiochemical properties copolymer formaldehyde ratio towards (CP 1–4 NPs). Following recruitment polymer surface, explored how this process influenced stiffness nanoparticle atomic force microscopy (AFM), factor crucial for in vitro vivo studies. Our objective ensure full functionality inherent parent maintained without allowing overshadow chitosan's unique cationic while improving neutral pH. Hence, CP 2 NP chosen. demonstrate efficacy good carrier administered dose 3 mg/kg contrast which given at 5 mg/kg. In studies revealed potency encapsulated cells severe necrotic effect following treatment superior auranofin. conclusion, chitosan-g-PEG potential be an excellent system increasing its effectiveness potentially reducing limitations.

Language: Английский

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Targeting PAX8 sensitizes ovarian cancer cells to ferroptosis by inhibiting glutathione synthesis

APOPTOSIS, Journal Year: 2024, Volume and Issue: 29(9-10), P. 1499 - 1514

Published: June 9, 2024

Language: Английский

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Antiproliferative effects, Mechanism of Action and Tumor Reduction Studies in a Lung Cancer Xenograft Mouse Model of an Organometallic Gold(I) Alkynyl Complex

RSC Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Organometallic complexes offer a wide range of properties like structural variety, reaction kinetics, tunable lipophilicity and alternate mechanisms activation under physiological conditions compared to platinum chemotherapeutics are thus...

Language: Английский

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The gold complex auranofin sensitizes platinum resistant epithelial ovarian cancer cells to cisplatin

Biochemistry and Biophysics Reports, Journal Year: 2025, Volume and Issue: 42, P. 101996 - 101996

Published: April 1, 2025

Language: Английский

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Pro-Oxidant Auranofin and Glutathione-Depleting Combination Unveils Synergistic Lethality in Glioblastoma Cells with Aberrant Epidermal Growth Factor Receptor Expression

Cancers, Journal Year: 2024, Volume and Issue: 16(13), P. 2319 - 2319

Published: June 25, 2024

Glioblastoma (GBM) is the most prevalent and advanced malignant primary brain tumor in adults. GBM frequently harbors epidermal growth factor receptor (EGFR) wild-type (EGFRwt) gene amplification and/or EGFRvIII activating mutation. EGFR-driven relies on thioredoxin (Trx) glutathione (GSH) antioxidant systems to withstand excessive production of reactive oxygen species (ROS). The impact EGFRwt or overexpression response a Trx/GSH co-targeting strategy unknown. In this study, we investigated context EGFR GBM. Auranofin reductase (TrxR) inhibitor, FDA-approved for rheumatoid arthritis. L-buthionine-sulfoximine (L-BSO) inhibits GSH synthesis by targeting glutamate–cysteine ligase catalytic (GCLC) enzyme subunit. We analyzed mechanisms cytotoxicity auranofin interaction between L-BSO U87MG, U87/EGFRwt, U87/EGFRvIII isogenic cell lines. ROS-dependent effects were assessed using N-acetylsteine. show that decreased TrxR1 activity increased ROS. vitality colony formation protein polyubiquitination through mechanisms, suggesting role ROS auranofin-induced three PARP-1 cleavage was associated with downregulation cells. Remarkably, combination induced significant depletion intracellular synergistic regardless overexpression. Nevertheless, molecular modulated different extent among exhibited prominent increase, P-AKT(Ser-473), AKT decrease along drastic downregulation. U87/EGFRwt displayed lower basal levels DNA damage compared U87MG Our study provides evidence vitro. Unraveling sensitivity EGFR-overexpressing cells alone, combination, supports rationale repurpose promising pro-oxidant treatment

Language: Английский

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Pyrroloquinoline Quinone Alleviates Mitochondria Damage in Radiation-Induced Lung Injury in a MOTS-c-Dependent Manner

Journal of Agricultural and Food Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 11, 2024

Radiation-induced lung injury (RILI) is a prevalent complication of thoracic tumor radiotherapy and accidental radiation exposure. Pyrroloquinoline quinone (PQQ), novel vitamin B, plays crucial role in delaying aging, antioxidation, anti-inflammation, antiapoptosis. This study aims to investigate the protective effect mechanisms PQQ against RILI. C57BL/6 mice were exposed 20 Gy dose X-ray on entire thorax with or without daily oral administration for 2 weeks. effectively mitigated radiation-induced tissue damage, inflammation, oxidative stress, epithelial cell apoptosis. Additionally, significantly inhibited stress mitochondrial damage MLE-12 cells. Mechanistically, upregulated mRNA protein levels MOTS-c irradiated Knockdown by siRNA substantially attenuated effects In conclusion, alleviates RILI preserving function through MOTS-c-dependent mechanism, suggesting that may serve as promising nutraceutical intervention

Language: Английский

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Cisplatin kills ovarium cancer cells through the TRPV1-mediated mitochondrial oxidative stress and apoptosis: TRPV1 inhibitor role of eicopentotaneoic acid

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 3, 2024

The most commonly used treatment, cisplatin (Cisp), causes excessive Ca²⁺ influx mediated by TRPV1 and produces a high concentration of mitochondrial free reactive oxygen radicals (mROS). In clinical trials, it can be with other adjuvant medicinal agents to increase safety efficacy. Although there are contradictory findings, eicosapentaenoic acid (EPA) as an has been demonstrated suppress the proliferation ovarian cancer cells. We assessed effects EPA Cisp incubations on oxidant, lysosomal injury, apoptotic values in OVCAR-3 tumor cell line activating TRPV1. Five groups were induced (25 µM for 24h), (100 + EPA, antagonist (capsazepine, CPZ). discovered that, comparison control cells, Cisp-mediated upregulation protein is downregulated CPZ, but mediates greater TRPV1-induced entry major mROS cells that cause activation include increases decreases glutathione, glutathione peroxidase, function, viability, number. response capsaicin, stimulation Zn²⁺ overload, which followed caspase-3/-8/-9, apoptosis, however, these less pronounced CPZ groups. To sum up, we first showed kills stimulating TRPV1, even while blocking channel reduced anti-cancer Cisp. stimulators together may provide alternative method killing

Language: Английский

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The Inhibition Mechanism of Auranofin on Thioredoxin Reductase 1 at the Molecular Level: A New Use of the Old Drug

Published: Jan. 1, 2024

Auranofin (AF), an established gold (I) complex historically utilized in rheumatoid arthritis treatment, is being repurposed as a novel anticancer agent. This investigation assesses the chemosensitizing capacity of AF to potentiate cytotoxic effects doxorubicin (DOX) melanoma cell models, including drug-sensitive (B16F10) and multidrug-resistant (B16F10/ADR) variants. Our findings reveal that cotreatment with DOX markedly augments antitumor efficacy, evidenced by diminished viability augmented apoptotic rates. synergism attributed AF's ability inhibit thioredoxin reductase 1 (TrxR1), thereby compromising antioxidant defenses tumor cells elevating intracellular reactive oxygen species (ROS), which turn enhances pathways. Significantly, treatment mitigates heightened TrxR activity DOX-resistant cells, intensifying pro-oxidant culminating increased ROS production cellular demise.Employing molecular docking, dynamics (MD) simulations, surface plasmon resonance (SPR) assays, we systematically delineated interaction between TrxR1. data indicate exhibits high-affinity binding selenocysteine residue within catalytic site TrxR1, footprint partially overlaps endogenous substrate, (Trx), yet greater avidity. unique configuration instrumental impede reduction Trx thus instigating response cancer cells.In summation, this study underscores potential surmounting multidrug resistance therapy through redox modulation elucidates its mechanism action on These pave way for clinical application chemosensitizer, offering approach augment efficacy existing chemotherapy regimens.

Language: Английский

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Metal (au, Pt, Pd, Ni) Bis(dithiolene) complexes as dual-action agents combating cancer and trypanosomatid infections

Journal of Inorganic Biochemistry, Journal Year: 2024, Volume and Issue: 264, P. 112788 - 112788

Published: Nov. 29, 2024

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