Cuproptosis Induced by ROS Responsive Nanoparticles with Elesclomol and Copper Combined with αPD‐L1 for Enhanced Cancer Immunotherapy

Advanced Materials, Journal Year: 2023, Volume and Issue: 35(22)

Published: March 14, 2023

Cuproptosis is a new cell death that depends on copper (Cu) ionophores to transport Cu into cancer cells, which induces death. However, existing are small molecules with short blood half-life making it hard enough cells. Herein, reactive oxygen species (ROS)-sensitive polymer (PHPM) designed, used co-encapsulate elesclomol (ES) and form nanoparticles (NP@ESCu). After entering ES Cu, triggered by excessive intracellular ROS, readily released. work in concerted way not only kill cells cuproptosis, but also induce immune responses. In vitro, the ability of NP@ESCu efficiently cuproptosis investigated. addition, change transcriptomes treated explored RNA-Seq. vivo, found mice model subcutaneous bladder cancer, reprograming tumor microenvironment. Additionally, further combined anti-programmed protein ligand-1 antibody (αPD-L1). This study provides first report combining nanomedicine can αPD-L1 for enhanced therapy, thereby providing novel strategy future therapy.

Language: Английский

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Biofilm Microenvironment‐Responsive Self‐Assembly Nanoreactors for All‐Stage Biofilm Associated Infection through Bacterial Cuproptosis‐like Death and Macrophage Re‐Rousing

Advanced Materials, Journal Year: 2023, Volume and Issue: 35(36)

Published: June 1, 2023

Bacterial biofilm-associated infections (BAIs) are the leading cause of prosthetic implant failure. The dense biofilm structure prevents antibiotic penetration, while highly acidic and H2 O2 -rich microenvironment (BME) dampens immunological response antimicrobial macrophages. Conventional treatments that fail to consistently suppress escaping planktonic bacteria from result in refractory recolonization, allowing BAIs persist. Herein, a BME-responsive copper-doped polyoxometalate clusters (Cu-POM) combination with mild photothermal therapy (PTT) macrophage immune re-rousing for BAI eradication at all stages is proposed. self-assembly Cu-POM BME converts endogenous toxic ·OH through chemodynamic (CDT) generates PTT effect induce bacterial metabolic exuberance, resulting loosening membrane bacteria, enhancing copper transporter activity increasing intracellular flux. Metabolomics reveals overload restricts TCA cycle peroxide accumulation, promoting cuproptosis-like death. CDT macrophages scavenge disintegration enhanced chemotaxis phagocytosis. Overall, promotes death via interference, also further elimination, all-stage clearance providing new reference future clinical application.

Language: Английский

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Fluorescent Probes for Biological Species and Microenvironments: from Rational Design to Bioimaging Applications

Accounts of Chemical Research, Journal Year: 2023, Volume and Issue: 56(3), P. 258 - 269

Published: Jan. 18, 2023

Some important biological species and microenvironments maintain a complex delicate dynamic balance in life systems, participating the regulation of various physiological processes playing indispensable roles maintaining healthy development living bodies. Disruption their homeostasis organisms can cause diseases even death. Therefore, real time monitoring these during different pathological is great significance. Fluorescent-probe-based techniques have been recognized as one most powerful tools for imaging samples. In this Account, we introduce representative works from our group field fluorescent probes capable detecting metal ions, small bioactive molecules, microenvironment. The design strategies molecule applications will be discussed. By regulating strategy mechanism (e.g., ICT, PeT, FRET) electronic spectral characteristics platforms, chemical show high selectivity diverse functions, which used processes. Through exploration rational response strategy, combined with variety techniques, such super-resolution imaging, photoacoustic (PA) etc., realized multimode analytes subcellular level to vivo level, provides means study functions microenvironments. This Account aims offer insights inspiration novel could provide biology. Overall, represent series turn-on/turn-off/ratiometric fluorescent/PA visually dynamically trace cells that seek higher resolution depth molecular improve diagnostic methods clarify new discoveries related Our future efforts devoted developing multiorganelle targeted organelle interaction employing dual-mode NIR II PA investigate treat at levels.

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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ATF3/SPI1/SLC31A1 Signaling Promotes Cuproptosis Induced by Advanced Glycosylation End Products in Diabetic Myocardial Injury

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1667 - 1667

Published: Jan. 14, 2023

Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by persistent hyperglycemia play an essential role cardiotoxicity. To clarify whether cuproptosis was involved AGEs-induced cardiotoxicity, we analyzed the toxicity of AGEs and AC16 cardiomyocytes STZ-induced or db/db-diabetic mouse models. The results showed that ionophore elesclomol cardiomyocytes. It only rescued chelator tetrathiomolybdate rather than other cell death inhibitors. Intriguingly, triggered cardiomyocyte aggravated it when incubated with CuCl2 elesclomol-CuCl2. Moreover, increased intracellular accumulation exhibited features cuproptosis, including loss Fe-S cluster proteins (FDX1, LIAS, NDUFS8 ACO2) decreased lipoylation DLAT DLST. These effects were accompanied mitochondrial oxidative respiration, downregulated respiratory chain complex, ATP production suppressed complex I III activity. Additionally, promoted upregulation importer SLC31A1. We predicted ATF3 and/or SPI1 might be transcriptional factors SLC31A1 online databases validated ATF3/SPI1 overexpression. In mice, increases blood heart observed cardiac dysfunction. protein mRNA profile changes hearts consistent cuproptosis. Our findings showed, for first time, excessive diabetes upregulated ATF3/SPI1/SLC31A1 signaling, thereby disturbing homeostasis promoting Collectively, novel mechanism alternative potential therapeutic target DCM.

Language: Английский

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Cuproptosis: A novel therapeutic target for overcoming cancer drug resistance

Drug Resistance Updates, Journal Year: 2023, Volume and Issue: 72, P. 101018 - 101018

Published: Nov. 11, 2023

Cuproptosis is a newly identified form of cell death driven by copper. Recently, the role copper and triggered in pathogenesis cancers have attracted attentions. has garnered enormous interest cancer research communities because its great potential for therapy. Copper-based treatment exerts an inhibiting tumor growth may open door chemotherapy-insensitive tumors. In this review, we provide critical analysis on homeostasis dysregulation development progression cancers. Then core molecular mechanisms cuproptosis discussed, followed summarizing current understanding copper-based agents (copper chelators, ionophores, complexes-based dynamic therapy) treatment. Additionally, summarize emerging data ionophores to subdue chemotherapy resistance different types We also review small-molecule compounds nanoparticles (NPs) that kill cells inducing cuproptosis, which will shed new light anticancer drugs through future. Finally, important concepts pressing questions future should be focused were discussed. This article suggests targeting could novel antitumor therapy strategy overcome drug resistance.

Language: Английский

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Potential of Copper and Copper Compounds for Anticancer Applications

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(2), P. 234 - 234

Published: Feb. 3, 2023

Inducing cancer cell death has always been a research hotspot in life sciences. With the continuous deepening and diversification of related research, potential value metal elements inducing explored. Taking iron as an example, ferroptosis, mainly characterized by increasing load driving production large amounts lipid peroxides eventually leading to death, recently attracted great interest community. After iron, copper, trace element, received extensive attention especially tumor death. Copper its complexes can induce autophagy or apoptosis cells through variety different mechanisms action (activation stress pathways, arrest cycle, inhibition angiogenesis, cuproptosis, paraptosis), which are promising therapy have become new hotspots treatment research. This article reviews main applications novel copper compound-induced focusing on compounds their anticancer applications.

Language: Английский

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4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to promote cuproptosis in colorectal cancer

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 159, P. 114301 - 114301

Published: Jan. 25, 2023

Cuproptosis, a novel copper-induced cell death pathway, is linked to mitochondrial respiration and mediated by protein lipoylation. The discovery of cuproptosis unfolds new areas investigation, particularly in cancers. present study aimed explore the role colorectal cancer progression. genetic alterations colon were evaluated using database. MTT assays, colony formation, flow cytometry used examine effect elesclomol-Cu 4-Octyl itaconate (4-OI) on oxaliplatin-resistant viability. anti-tumor elesclomol with 4-OI was verified vivo assay. results showed that FDX1, SDHB, DLAT, DLST genes more highly expressed normal tissues than those primary tumor tissues. Patients high expressions these had better prognosis. Using assay formation analysis, pulse treatment significant inhibition viability HCT116, LoVo, HCT116-R cells. In addition, revealed significantly promoted apoptosis. Tetrathiomolybdate, copper chelator, markedly inhibited cuproptosis. Subsequently, we found 2-deoxy-D-glucose, glucose metabolism inhibitor, sensitized Furthermore, galactose further Interestingly, enhanced which irrelevant ROS production, apoptosis, necroptosis, or pyroptosis pathways. Aerobic glycolysis through GAPDH, one key enzymes glycolysis, sensitizing Meanwhile, FDX1 knockdown weakened ability promote experiments, effects. These indicated rapidly halted growth cells line. Importantly, aerobic targeting GAPDH

Language: Английский

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The role of lipid metabolic reprogramming in tumor microenvironment

Theranostics, Journal Year: 2023, Volume and Issue: 13(6), P. 1774 - 1808

Published: Jan. 1, 2023

Metabolic reprogramming is one of the most important hallmarks malignant tumors.Specifically, lipid metabolic has marked impacts on cancer progression and therapeutic response by remodeling tumor microenvironment (TME).In past few decades, immunotherapy revolutionized treatment landscape for advanced cancers.Lipid plays pivotal role in regulating immune to immunotherapy.Here, we systematically reviewed characteristics, mechanism, cells TME, appraised effects various cell death modes (specifically ferroptosis) metabolism, summarized antitumor therapies targeting metabolism.Overall, profound microenvironment; therefore, may lead development innovative clinical applications including sensitizing immunotherapy.

Language: Английский

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Copper homeostasis and cuproptosis in cardiovascular disease therapeutics

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(9), P. 573 - 585

Published: July 25, 2023

Language: Английский

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