Regulation of ferroptosis by lipid metabolism

Trends in Cell Biology, Journal Year: 2023, Volume and Issue: 33(12), P. 1077 - 1087

Published: July 3, 2023

Language: Английский

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Sensitization of cancer cells to ferroptosis coincident with cell cycle arrest

Cell chemical biology, Journal Year: 2023, Volume and Issue: 31(2), P. 234 - 248.e13

Published: Nov. 13, 2023

Language: Английский

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Yi-qi-hua-yu-jie-du decoction induces ferroptosis in cisplatin-resistant gastric cancer via the AKT/GSK3β/NRF2/GPX4 axis

Phytomedicine, Journal Year: 2023, Volume and Issue: 123, P. 155220 - 155220

Published: Nov. 18, 2023

Language: Английский

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Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(7), P. 2815 - 2853

Published: April 24, 2024

Regulated cell death (RCD) is a controlled form of orchestrated by one or more cascading signaling pathways, making it amenable to pharmacological intervention. RCD subroutines can be categorized as apoptotic non-apoptotic and play essential roles in maintaining homeostasis, facilitating development, modulating immunity. Accumulating evidence has recently revealed that evasion frequently the primary cause tumor survival. Several have garnered attention promising cancer therapies due their ability induce regression prevent relapse, comparable apoptosis. Moreover, they offer potential solutions for overcoming acquired resistance tumors toward drugs. With an increasing understanding underlying mechanisms governing these subroutines, growing number small-molecule compounds targeting single multiple pathways been discovered, providing novel strategies current therapy. In this review, we comprehensively summarized regulatory emerging mainly including autophagy-dependent death, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition (MPT)-driven necrosis, entotic NETotic lysosome-dependent immunogenic (ICD). Furthermore, focused on discussing related compounds. brief, insightful findings may provide valuable guidance investigating individual collaborative approaches towards different ultimately driving discovery target significantly enhance future therapeutics.

Language: Английский

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ML162 derivatives incorporating a naphthoquinone unit as ferroptosis/apoptosis inducers: Design, synthesis, anti-cancer activity, and drug-resistance reversal evaluation

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 270, P. 116387 - 116387

Published: April 1, 2024

Language: Английский

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Research progress on GPX4 targeted compounds

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 274, P. 116548 - 116548

Published: May 31, 2024

Language: Английский

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Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches

Drug Design Development and Therapy, Journal Year: 2024, Volume and Issue: Volume 18, P. 2485 - 2529

Published: June 1, 2024

Abstract: Ferroptosis, a unique form of programmed cell death, is initiated by an excess iron accumulation and lipid peroxidation-induced damage. There growing body evidence indicating that ferroptosis plays critical role in the advancement tumors. The increased metabolic activity higher levels tumor cells make them particularly vulnerable to ferroptosis. As result, targeted induction becoming increasingly promising approach for cancer treatment. This review offers overview regulatory mechanisms ferroptosis, delves into mechanism action traditional small molecule inducers their effects on various In addition, latest progress inducing using new means such as proteolysis-targeting chimeras (PROTACs), photodynamic therapy (PDT), sonodynamic (SDT) nanomaterials summarized. Finally, this discusses challenges opportunities development ferroptosis-inducing agents, focusing discovering targets, improving selectivity, reducing toxic side effects. Keywords: inducers, molecules, PROTACs, PDT, SDT,

Language: Английский

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Targeting ferroptosis resistance resensitizes metastatic HR⁺HER2⁻ breast cancer cells to palbociclib‐hormone therapy

Cancer Communications, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Metastatic hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) breast cancer often develops resistance to first-line treatment, typically combining cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) with therapy (HT) [1, 2]. After an initial response, most patients become resistant, compensatory mechanisms are not fully uncovered [3]. To address this, we analyzed HR+ resistant CAMA1 747D cells using whole-exome RNA sequencing, supplemented by proteomics target validation samples. Additionally, conducted combination trials xenografts patient-derived (PDXs). Detailed study designs methods provided in the Supplementary file. In a cohort of 27 metastatic cancer, observed reduced progression-free survival second- third-line therapies following progression post palbociclib-HT treatment (Supplementary Figure S1A Table S1). Resistant tumors showed estrogen alpha (ERα) progesterone (PR) increased proliferation rates S1B-D). T47D cells, treated palbociclib fulvestrant (PF) for 2 years, developed (CAMA1-PFR T47D-PFR) confirmed assays elevated half-maximal inhibitory concentrations. exhibited levels ERα retinoblastoma protein S2). Exome analysis revealed no drug resistance-related mutations Tables S2-S3), suggesting non-genetic factors. sequencing DMSO or PF 20 days T47D-PFR 1,172 upregulated genes 824 downregulated S3A). Gene set enrichment indicated fatty acid localization S3B), heatmap showing uptake metabolism-related genes, such as binding protein-6 (FABP6), FABP7, cluster differentiation-36 (CD36), proteasome proliferator-activated receptor-gamma (PPARγ) (Figure 1A). Lipid droplets accumulated PF-treated parental PF-resistant 1B S3C). FABP6 were CD36 overexpression unique at both mRNA 1C S3D-E), that lipid might be adaptive response oxidative stress [4, 5]. This was supported reactive oxygen species (ROS) 1D). Furthermore, proteomic biopsies functional network 11 stress-triggered proteasomes S4A S4-S5) indicators [6]. Immunohistochemistry validated subunit type-7 (PSMA7) S4B). Ferroptosis inducers overcome HR+HER2− palbociclib-hormone therapy. (A) Heatmap (red) (blue) during days, (T47D-PFR) after continuous compared vehicle (DMSO). All represented had P value < 0.05. (B) droplet detection BODIPY 493/503 staining CAMA1-PFR years. DAPI used visualize nuclei. (C) Western blot (D) Measurement ROS DCFDA assay 5 PF. Continuous discontinued 3 prior assay. (E) GPX4 CAMA1, ZR75.1 CAMA1-PFR, ZR75.1-PFR (F) (images) quantification (bar chart) GPX4-positive taken before (*P 0.05). (G) Assessment cell according fold change confluence DMSO, ferroptosis inducer RSL3 (1 µmol/L), inhibitor Trolox (10 7 days. (H) different combinations (P) (0.3 (30 nmol/L), eprenetapopt (Ep) (25 µmol/L) (I, J) Tumor curves (6 mice per group) (I) (8 (J) 75 mg/kg daily, 50 once week, 150 mg/kg, times/day 100 intratumoral injection every two weeks (***P 0.001). (K) Growth palbociclib-HT-naïve HBCx-124 PDXs (5 (L) palbociclib-HT-resistant HBCx-180 times/day. The difference between measured tumor volumes significant "vehicle" group + (FPE) from Day 25 until end experiment (P evolution formula is (Vf − V0 / V0) × 100%, where volume Vf final each time point. Abbreviations: CD36, differentiation 36; DAPI, 4′,6-diamidino-2-phenylindole; DCFDA, 2′,7′-Dichlorofluorescin Diacetate; dimethyl sulfoxide; Ep, eprenetapopt; FABP6, 6; GPX4, Glutathione peroxidase 4; HR+HER2−, positive receptor-2 negative; HT, therapy; PDX, xenograft; PF, palbociclib-fulvestrant; RSL3, palbociclib-fulvestrant-RSL3; PFE, palbociclib-fulvestrant-eprenetapopt; ROS, species, ras-selective lethal small molecule 3; Trolox, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. We investigated whether affected ferroptosis—a type non-apoptotic death linked peroxidation. protein, main protector against ferroptosis, overexpressed even wash-out, changes 1E S5A-C). Silencing expression S5D-F), indicating their reliance on GPX4. also 1F). Cells RAS-selective (RSL3) antioxidant insensitive whereas high sensitivity 1G). reversed RSL3's effect lines 1G), highlighting role proliferation. Due unverified safety RLS3, (Ep), p53 activator GSH depletory [7] proven safe hematological [8]. vitro, sensitive while insensitive; higher 1H). investigate pharmacologically induced palbociclib-fulvestrant vivo, nude implanted pellets. its low pharmacokinetics mouse plasma [9], administered via injection. Mice vehicle, (PFEp), (PF-RSL3). effectively inhibited xenografts, 1I J). alone did affect growth, PF-RSL3 demonstrated strong antitumor 1J), sensitizes vice versa. Similarly, Ep inhibit but completely abolished 1J). evaluate effects death, assessed Ki67, caspase-3 hydroxynonenal (HNE) immunohistochemistry. Parental decrease caspase-3, either marker PFEp, S6A-D). HNE labeling PF- vehicle-treated S6E), moderately significantly PFEp S6F), potential ferroptosis. No treatments type, although basal S6G-J). strengthen translational impact our findings, (PDXs) without S7A) [10]. Consistent samples, PDX model (HBCx-180) (HBCx-124) S7B). While unaffected S7C), specific transcriptional/translational regulation differing vitro vivo contexts. model, all (n = 5) responded well added benefit partial monotherapy 1K). Conversely, differences groups onward 0.05) 1L). These results confirm adding produces effect. Ki67 decreased S8A-B). Aside reduction none conditions S8C-D), apoptosis HBCx-180. suggested promoted HBCx-124, only increase S8E-F). slightly significance vulnerability attributed PFEp. p53-dependent excluded, similar PDXs, S9). Finally, addition induce renal, hepatic, toxicity S10). conclusion, vulnerable inducers, collateral promise developing pro-ferroptosis agents treating drug-resistant S11). Conception design: CP NES. Development methodology: CP, LMR, Acquisition data: RT, CW, RJ, AR, JC, CJ, SG, SB, AD, PD, LM EM. Analysis interpretation data (e.g., statistical analysis, biostatistics): DB, GM, CJ Writing, review, and/or revision manuscript: GJ, AN Study supervision: GJ authors thank Cell Imaging Core Facility GIGA institute Incucyte fluorescence microscopy experiments; Isabelle Dasoul, Emilie Feyereisen, Erika Konradowski Nathalie Lefin technical support; Maud Piron enrolling patients; Hélène Schroeder correcting file sent ethics committee Biobank Liège University providing Latifa Karim Manon Deckers Sequencing Platform (ULiège, Belgium) help advice; Erik Maquoi image acquisition Nanolive Louis Baudin (Animascience, Liège, graphical abstract. declare competing interest except Dr. Guy Jerusalem, who declares receiving grant support, paid his institution, advisory board fees, lecture travel writing assistance Novartis, Roche, Pfizer. Disclosure full text this article. other conflicts relevant article reported. work grants National Fund Scientific Research (NFSR-FNRS) Belgium (NES: PDR T.023020; CDR J.0178.22); credit sectorial Liege FSR-S-SS-22/61; FSR-S-SS-22/64); Foundation Contre le Cancer, (NES AN: FCC-2022-181). deposited GEO-NCBI depository accession number: GSE270021 registered BioProject database identification PRJNA1027140 Proteomic PRIDE PXD053296. support findings available corresponding author upon reasonable request. A protocol approved institutional Ethics Committee Hospital (Liege, Belgium; file#2018/312) use samples study, ethical guidelines Declaration Helsinki followed. has authorized May 15, 2019, retrospectively stored biobank anonymized clinical associated these biopsies. noted non-interventional within scope law 7, 2004, experiments beings thus require informed consents. For animal procedures performed Federation European Laboratory Animal Sciences Associations (FELASA) accredited facility (University Liege, (project authorization no. 2078). Institute Curie, accordance rules French 02163.02). Please note: publisher responsible content functionality any supporting information supplied authors. Any queries (other than missing content) should directed

Language: Английский

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Development of a Highly Selective Ferroptosis Inducer Targeting GPX4 with 2-Ethynylthiazole-4-carboxamide as Electrophilic Warhead

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 68(3), P. 3309 - 3323

Published: Jan. 30, 2025

A highly selective ferroptosis inducer with drug-like properties can significantly advance the research on inducing for anticancer treatment. We previously reported a active GPX4 inhibitor 26a, but its activity and stability need further improvement. In this work, novel (R)-9i more potent cytotoxicity (IC50 = 0.0003 μM against HT1080) selectivity (selectivity index 24933) was gained via electrophilic warhead screening structure-based optimization. The cellular thermal shift assay (CETSA) indicated that could stabilize Tm value of 6.2 °C. Furthermore, showed strong binding affinity (KD 20.4 nM). More importantly, has favorable pharmacokinetic than which endowed potential in antitumor as tool drug study ferroptosis. Associated these, treatment inhibited tumor growth xenograft mouse model without detectable toxicity.

Language: Английский

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Mechanisms of ferroptosis sensitization and resistance

Developmental Cell, Journal Year: 2025, Volume and Issue: 60(7), P. 982 - 993

Published: April 1, 2025

Language: Английский

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