Elesclomol: a copper ionophore targeting mitochondrial metabolism for cancer therapy

Journal of Experimental & Clinical Cancer Research, Год журнала: 2022, Номер 41(1)

Опубликована: Сен. 12, 2022

Abstract Elesclomol is an anticancer drug that targets mitochondrial metabolism. In the past, elesclomol was recognized as inducer of oxidative stress, but now it has also been found to suppress cancer by inducing cuproptosis. Elesclomol’s activity determined dependence on The metabolism stem cells, cells resistant platinum drugs, proteasome inhibitors, molecularly targeted and with inhibited glycolysis significantly enhanced. exhibited tremendous toxicity all three kinds cells. Elesclomol's highly dependent its transport extracellular copper ions, a process involved in discovery cuproptosis perfected specific suppressor mechanism elesclomol. For some time, failed yield favorable results oncology clinical trials, safety application confirmed. Research progress relationship between elesclomol, provides possibility explore reapplication clinic. New trials should selectively target types high attempt combine platinum, or inhibitors. Herein, particular will be presented, which may shed light better tumor treatment.

Язык: Английский

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A Hollow Amorphous Bimetal Organic Framework for Synergistic Cuproptosis/Ferroptosis/Apoptosis Anticancer Therapy via Disrupting Intracellular Redox Homeostasis and Copper/Iron Metabolisms

Advanced Functional Materials, Год журнала: 2022, Номер 32(40)

Опубликована: Июль 30, 2022

Abstract Cuproptosis is a very newly recognized regulated cell death modality that distinct from known mechanisms and shows enormous prospect in cancer treatment. However, its efficacy copper‐dependent restricted by strictly copper metabolism. Herein, novel copper/iron hybrid hollow amorphous metal organic framework (HaMOF) developed as an oxidative stress amplifier metabolic disrupter for synergistic cuproptosis/ferroptosis/apoptosis anticancer therapy. The HaMOF fabricated Cu 2+ , 3,3′‐dithiobis(propionohydrazide) Fe 3+ via unsaturated coordination‐etching integration strategy, then doxorubicin loaded followed surface decoration with hyaluronan. obtained DOX@Fe/CuTH exhibits tumor microenvironment‐triggered catalytic therapeutic property, wherein it can amplify cellular simultaneously boosting H 2 O production depleting glutathione. Moreover, cause mitochondrial dysfunction downregulate the expressions of transporter ATP7A iron FPN 1, thereby leading to disorders high retentions cytoplasm •OH generation. overloaded lipoylated protein dihydrolipoamide S‐acetyltransferase aggregation lead cuproptosis. Collectively, both augmented induce potent ferroptosis, which synergizes cuproptosis DOX‐mediated apoptosis efficiently suppress growth. This bimetallic nanoplatform provides new paradigm boost cuproptosis‐related therapies.

Язык: Английский

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Stimuli-activatable nanomedicine meets cancer theranostics

Theranostics, Год журнала: 2023, Номер 13(15), С. 5386 - 5417

Опубликована: Янв. 1, 2023

Stimuli-activatable strategies prevail in the design of nanomedicine for cancer theranostics.Upon exposure to endogenous/exogenous stimuli, stimuli-activatable could be self-assembled, disassembled, or functionally activated improve its biosafety and diagnostic/therapeutic potency.A myriad tumor-specific features, including a low pH, high redox level, overexpressed enzymes, along with exogenous physical stimulation sources (light, ultrasound, magnet, radiation) have been considered nano-medicinal products.Recently, novel stimuli explored elegant designs emerged nanomedicine.In addition, multi-functional theranostic has employed imaging-guided image-assisted antitumor therapy.In this review, we rationalize development clinical pressing needs.Stimuli-activatable self-assembly, disassembly functional activation approaches developing realize better efficacy are elaborated state-of-the-art advances their structural detailed.A reflection, status, future perspectives provided.

Язык: Английский

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Copper-Based Metal–Organic Framework Overcomes Cancer Chemoresistance through Systemically Disrupting Dynamically Balanced Cellular Redox Homeostasis

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(11), С. 4799 - 4809

Опубликована: Фев. 22, 2022

Chemodrug resistance is a major reason accounting for tumor recurrence. Given the mechanistic complexity of chemodrug resistance, molecular inhibitors and targeting drugs often fail to eliminate drug-resistant cancer cells, sometimes even promote chemoresistance by activating alternative pathways. Here, exploiting biochemical fragility high-level but dynamically balanced cellular redox homeostasis in we design nanosized copper/catechol-based metal-organic framework (CuHPT) that effectively disturbs this tilting balance toward oxidative stress. Within CuHPT starts disassembly triggered persistent consumption glutathione (GSH). simultaneously releases two structural elements: catechol ligands reductive copper ions (Cu+). Both them cooperatively function amplify production intracellular radical species (ROS) via auto-oxidation Fenton-like reactions through exhausting GSH. By drastically heightening stress, exhibits selective potent cytotoxicity multiple cells. Importantly, inhibits vivo growth doubles survival time tumor-bearing mice. Thus, along with CuHPT's good biocompatibility, our biochemical, cell biological, preclinical animal model data provide compelling evidence supporting notion copper-based MOF predesigned smart therapeutic against cancers precisely deconstructing their homeostasis.

Язык: Английский

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Ferroptosis Detection: From Approaches to Applications

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(35)

Опубликована: Фев. 25, 2023

Abstract Understanding the intricate molecular machinery that governs ferroptosis and leveraging this accumulating knowledge could facilitate disease prevention, diagnosis, treatment, prognosis. Emerging approaches for in situ detection of major regulators biological events across cellular, tissue, living subjects provide a multiscale perspective studying ferroptosis. Furthermore, advanced applications integrate latest technologies hold tremendous promise research. In review, we first briefly summarize mechanisms key underlying Ferroptosis are then presented to delineate their design, action, applications. Special interest is placed on multifunctional platforms. Finally, discuss prospects challenges applications, with aim providing roadmap theranostic development broad range ferroptosis‐related diseases.

Язык: Английский

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A Biodegradable Iridium(III) Coordination Polymer for Enhanced Two‐Photon Photodynamic Therapy Using an Apoptosis–Ferroptosis Hybrid Pathway

Angewandte Chemie International Edition, Год журнала: 2022, Номер 61(28)

Опубликована: Май 9, 2022

Abstract The clinical application of photodynamic therapy is hindered by the high glutathione concentration, poor cancer‐targeting properties, drug loading into delivery systems, and an inefficient activation cell death machinery in cancer cells. To overcome these limitations, herein, formulation a promising Ir III complex biodegradable coordination polymer ( IrS NPs ) presented. nanoparticles were found to remain stable under physiological conditions but deplete disintegrate monomeric metal complexes tumor microenvironment, causing enhanced therapeutic effect. selectively accumulate mitochondria where trigger hybrid apoptosis ferroptosis pathways through photoinduced production singlet oxygen superoxide anion radicals. This study presents first example that can efficiently cause upon irradiation, providing innovative approach for therapy.

Язык: Английский

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Copper-doped MOF-based nanocomposite for GSH depleted chemo/photothermal/chemodynamic combination therapy

Chemical Engineering Journal, Год журнала: 2022, Номер 438, С. 135567 - 135567

Опубликована: Март 1, 2022

Язык: Английский

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Drug-induced oxidative stress in cancer treatments: Angel or devil?

Redox Biology, Год журнала: 2023, Номер 63, С. 102754 - 102754

Опубликована: Май 18, 2023

Oxidative stress (OS), defined as redox imbalance in favor of oxidant burden, is one the most significant biological events cancer progression. Cancer cells generally represent a higher level, which suggests dual therapeutic strategy by regulating status (i.e., pro-oxidant therapy and/or antioxidant therapy). Indeed, exhibits great anti-cancer capability, attributing to accumulation within cells, whereas restore homeostasis has been claimed fail several clinical practices. Targeting vulnerability pro-oxidants capable generating excessive reactive oxygen species (ROS) surfaced an important strategy. However, multiple adverse effects caused indiscriminate attacks uncontrolled drug-induced OS on normal tissues and drug-tolerant capacity some certain greatly limit their further applications. Herein, we review representative oxidative drugs summarize side organs, emphasizing that seeking balance between damage value exploiting next-generation OS-based chemotherapeutics.

Язык: Английский

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Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Янв. 3, 2024

Abstract Zinc metabolism at the cellular level is critical for many biological processes in body. A key observation disruption of homeostasis, often coinciding with disease progression. As an essential factor maintaining equilibrium, zinc has been increasingly spotlighted context development. Extensive research suggests zinc’s involvement promoting malignancy and invasion cancer cells, despite its low tissue concentration. This led to a growing body literature investigating metabolism, particularly functions transporters storage mechanisms during transportation under control two major transporter families: SLC30 (ZnT) excretion SLC39 (ZIP) intake. Additionally, this element predominantly mediated by metallothioneins (MTs). review consolidates knowledge on signaling underscores potential molecular pathways linking progression, special focus cancer. We also compile summary clinical trials involving ions. Given main localization cell membrane, targeted therapies, including small molecules monoclonal antibodies, offers promising avenues future exploration.

Язык: Английский

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Tumor Microenvironment-Activable Manganese-Boosted Catalytic Immunotherapy Combined with PD-1 Checkpoint Blockade

ACS Nano, Год журнала: 2022, Номер 16(12), С. 20400 - 20418

Опубликована: Ноя. 28, 2022

Immune checkpoint blockade (ICB) therapy has attracted widespread attention in cancer treatment. Due to the low immunogenicity and immune suppression state tumor microenvironment (TME), therapeutic effects are only moderate. Herein, a TME-activable manganese-boosted catalytic immunotherapy is designed for synergism with ICB kill tumors efficiently. The cell membrane (CM)-wrapping multienzyme-mimic manganese oxide (MnOx) nanozyme termed CM@Mn showed intrinsic peroxidase oxidase-like activities an acidic TME. These can generate toxic hydroxyl (•OH) superoxide radicals (•O2-) killing evoking immunogenic death (ICD). Furthermore, TME-responsive release of Mn2+ directly promotes dendritic maturation macrophage M1 repolarization, resulting reversal immunosuppressive TME into immune-activating environment. Additionally, hypoxia relief caused by catalase-like activity also contributes process reversal. Finally, robust tumor-specific T cell-mediated antitumor response occurs support PD-1 blockade. proliferation primary metastatic was inhibited, long-term memory effect induced. strategy outlined here may serve as promising candidate tumor-integrated

Язык: Английский

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