Molecular Self-Assembly of Bioorthogonal Aptamer-Prodrug Conjugate Micelles for Hydrogen Peroxide and pH-Independent Cancer Chemodynamic Therapy

Journal of the American Chemical Society, Journal Year: 2019, Volume and Issue: 142(2), P. 937 - 944

Published: Dec. 20, 2019

Chemodynamic therapy (CDT) has demonstrated new possibilities for selective and logical cancer intervention by specific manipulation of dysregulated tumorous free radical homeostasis. Current CDT methods largely rely on conversion endogenous hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals via classical Fenton or Haber–Weiss chemistry. However, their anticancer efficacies are greatly limited the requirement strong acidity efficient chemical reactions, insufficient H2O2, upregulated antioxidant defense to counteract radical-caused oxidative damage. Here, we present a concept whereby bioorthogonal chemistry prodrug combined create type aptamer drug conjugate (ApDC): aptamer-prodrug (ApPdC) micelle improved cancer-targeted CDT. The hydrophobic bases can not only promote self-assembly aptamers but also act as generators In depth mechanistic studies reveal that, unlike traditional systems, ApPdC micelles enable in situ activation self-cycling generation C-centered cells through cascading with no dependence either H2O2 pH, yet concurrently diminished cancerous antioxidation GSH depletion synergistic effect. We expect this work provide insights design targeted therapies radical-related molecular mechanisms.

Language: Английский

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The ferroptosis and iron-metabolism signature robustly predicts clinical diagnosis, prognosis and immune microenvironment for hepatocellular carcinoma

Cell Communication and Signaling, Journal Year: 2020, Volume and Issue: 18(1)

Published: Oct. 28, 2020

In this study, we comprehensively analyzed genes related to ferroptosis and iron metabolism construct diagnostic prognostic models explore the relationship with immune microenvironment in HCC.Integrated analysis, cox regression least absolute shrinkage selection operator (LASSO) method of 104 ferroptosis- metabolism-related HCC-related RNA sequencing were performed identify genes.Four (ABCB6, FLVCR1, SLC48A1 SLC7A11) identified models. Poorer overall survival (OS) was exhibited high-risk group than that low-risk both training cohort (P < 0.001, HR = 0.27) test 0.27). The successfully distinguished HCC from normal samples proliferative nodule samples. Compared groups, groups had higher TMB; fractions macrophages, follicular helper T cells, memory B neutrophils; expression CD83, B7H3, OX40 CD134L. As an inducer ferroptosis, erastin inhibited cell proliferation progression, it showed affect Th17 differentiation IL-17 signaling pathway through bioinformatics indicating a potential agent cancer immunotherapy.The based on four indicated superior predictive performance, new possibilities for individualized treatment patients. Video Abstract.

Language: Английский

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Iron Metabolism and Immune Regulation

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: March 23, 2022

Iron is a critical element for living cells in terrestrial life. Although iron metabolism strictly controlled the body, disturbance of homeostasis under certain type condition leads to innate and adaptive immune response. In immunity, regulates macrophage polarizations, neutrophils recruitment, NK activity. had an effect on activation differentiation Th1, Th2, Th17 CTL, antibody response B cells. this review, we focused regulation listed specific role polarization, T-cell activation, B-cells addition, correlations between several diseases such as cancer aging degenerative some therapeutic strategies targeting those are also discussed.

Language: Английский

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Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines

Oncogene, Journal Year: 2021, Volume and Issue: 40(8), P. 1425 - 1439

Published: Jan. 8, 2021

Abstract Dysregulated iron metabolism is a hallmark of many cancers, including glioblastoma (GBM). However, its role in tumor progression remains unclear. Herein, we identified coatomer protein complex subunit zeta 1 (COPZ1) as therapeutic target candidate which significantly dysregulated GBM cells. Overexpression COPZ1 was associated with increasing grade and poor prognosis glioma patients based on analysis expression data from the publicly available database The Cancer Genome Atlas ( P < 0.001). Protein levels were increased compared to non-neoplastic brain tissue samples immunohistochemistry western blot analysis. SiRNA knockdown suppressed proliferation U87MG, U251 P3#GBM vitro. Stable shRNA construct U87MG inhibited growth vivo by ~60% relative controls at day 21 after implantation Kaplan–Meier survival demonstrated that overall bearing animals 20.8 days (control) 27.8 (knockdown, 0.05). also led increase nuclear receptor coactivator 4 (NCOA4), resulting degradation ferritin, subsequent intracellular ferrous ultimately ferroptosis. These demonstrate critical mediator metabolism. COPZ1/NCOA4/FTH1 axis therefore novel for treatment human GBM.

Language: Английский

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Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases

Cells, Journal Year: 2020, Volume and Issue: 9(6), P. 1456 - 1456

Published: June 12, 2020

Iron is essential for all living organisms. Many iron-containing proteins and metabolic pathways play a key role in almost cellular physiological functions. The diversity of the activity function iron its associated pathologies based on bond formation with adjacent ligands overall structure complex or other biomolecules. control absorption, utilization, recycling excretion by ensures normal biologic activity. Abnormalities proteins, also processes can lead to an array diseases. These include deficiency, which affects more than quarter world’s population; hemoglobinopathies, are most common genetic disorders idiopathic hemochromatosis. catalyst free radical production oxidative stress implicated tissue damage pathologic conditions, cancer initiation progression, neurodegeneration many interaction dietary xenobiotic molecules, including drugs, may affect disease processes. Deferiprone, deferoxamine, deferasirox chelating drugs offer therapeutic solutions diseases metabolism overload cancer, detoxification metals pathology.

Language: Английский

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MiR-375 reduces the stemness of gastric cancer cells through triggering ferroptosis

Stem Cell Research & Therapy, Journal Year: 2021, Volume and Issue: 12(1)

Published: June 5, 2021

Gastric cancer stem cells (CSCs) are the main causes of metastasis and drug resistance. We previously indicated that miR-375 can inhibit Helicobacter pylori-induced gastric carcinogenesis; here, we aim to explore effects mechanisms on (GC) cell stemness.

Language: Английский

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SCD1/FADS2 fatty acid desaturases equipoise lipid metabolic activity and redox-driven ferroptosis in ascites-derived ovarian cancer cells

Theranostics, Journal Year: 2022, Volume and Issue: 12(7), P. 3534 - 3552

Published: Jan. 1, 2022

Rationale: Malignant ascites in peritoneal metastases is a lipid-enriched microenvironment and frequently involved the poor prognosis of epithelial ovarian cancer (EOC). However, detailed mechanisms underlying (OvCa) cells dictating their lipid metabolic activities promoting tumor progression remain elusive. Methods: The omental conditioned medium (OCM) was established to imitate or microenvironment. Mass spectrometry, RT-qPCR, IHC, western blot assays were applied evaluate human fatty acid desaturases expressions activities. Pharmaceutical inhibition genetic ablation SCD1/FADS2 performed observe oncogenic capacities. RNA sequencing, peroxidation, cellular iron, ROS, Mito-Stress examine ferroptosis. OvCa patient-derived organoid mouse model used combined effect inhibitors with cisplatin. Results: We found that two critical desaturases, stearoyl-CoA desaturase-1 (SCD1) acyl-CoA 6-desaturase (FADS2), aberrantly upregulated, accelerating aggressiveness ascites-derived cells. Lipidomic analysis revealed elevation unsaturated acids (UFAs) positively associated levels capacities In contrast, pharmaceutical retarded growth, stem cell (CSC) formation reduced platinum resistance. Inhibition directly downregulated GPX4 GSH/GSSG ratio, causing disruption cellular/mitochondrial redox balance subsequently, iron-mediated peroxidation mitochondrial dysfunction Conclusions: Combinational treatment cisplatin synergistically repressed dissemination, providing promising chemotherapeutic strategy against EOC metastases.

Language: Английский

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Ferroptosis inducer erastin sensitizes NSCLC cells to celastrol through activation of the ROS–mitochondrial fission–mitophagy axis

Molecular Oncology, Journal Year: 2021, Volume and Issue: 15(8), P. 2084 - 2105

Published: March 6, 2021

Despite recent progress in non-small-cell lung cancer (NSCLC) treatment, treatment outcomes remain poor, mainly because of resistance or toxicity. Erastin is a ferroptosis inducer that has shown promising cytotoxic effects various types cancers, including NSCLC. Celastrol triterpene extracted from the Tripterygium wilfordii exhibits potential anticancer activity. However, side celastrol are severe and limit its clinical application. Combination therapy strategy to overcome compensatory mechanisms unwanted off-target effects. In present study, we found erastin synergized with induce cell death at nontoxic concentrations. The combined significantly increased reactive oxygen species (ROS) generation, disrupted mitochondrial membrane potential, promoted fission. Furthermore, cotreatment initiated ATG5/ATG7-dependent autophagy, PINK1/Parkin-dependent mitophagy, expression heat shock proteins (HSPs) an HSF1-dependent manner. HSF1 knockdown further enhanced vitro inhibited tumor growth vivo. Our findings indicate combination may represent novel therapeutic regimen for patients NSCLC warrants evaluation.

Language: Английский

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Ferroptosis inducers enhanced cuproptosis induced by copper ionophores in primary liver cancer

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: June 6, 2023

Cuproptosis and ferroptosis are the two newly defined metal-related regulated cell death. However, crosstalk between cuproptosis is obscure.We analyzed effect of inducers on copper ionophores-induced death through CCK-8 assay. was studied using immunofluorescence protein soluble-insoluble fraction isolation. GSH assay, qRT-PCR western blot were adopted to explore machinery enhanced cuproptosis. And mouse xenograft model built detect synergy elesclomol-Cu sorafenib in vivo.Herein we found that erastin could enhance primary liver cancer cells by increasing dependent lipoylated aggregation. Mechanically, upregulated lipoylation via suppressing mitochondrial matrix-related proteases mediated ferredoxin 1 (FDX1) degradation, reduced intracellular chelator glutathione (GSH) synthesis inhibiting cystine importing.Our findings proposed combination ionophores co-targeting be a novel therapeutic strategy for cancer.

Language: Английский

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Ferroptosis as a potential target for cancer therapy

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(7)

Published: July 24, 2023

Abstract Ferroptosis is a recently discovered essential type of cell death that mainly characterized by iron overload and lipid peroxidation. Emerging evidence suggests ferroptosis double-edged sword in human cancer. However, the precise underlying molecular mechanisms their differential roles tumorigenesis are unclear. Therefore, this review, we summarize briefly present key pathways ferroptosis, paying special attention to regulation as well its dual role an oncogenic tumor suppressor event various cancers. Moreover, multiple pharmacological activators summarized, prospect targeting cancer therapy further elucidated.

Language: Английский

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