Regulated cell death (RCD) in cancer: key pathways and targeted therapies

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Aug. 13, 2022

Regulated cell death (RCD), also well-known as programmed (PCD), refers to the form of that can be regulated by a variety biomacromolecules, which is distinctive from accidental (ACD). Accumulating evidence has revealed RCD subroutines are key features tumorigenesis, may ultimately lead establishment different potential therapeutic strategies. Hitherto, targeting with pharmacological small-molecule compounds been emerging promising avenue, rapidly progressed in many types human cancers. Thus, this review, we focus on summarizing not only apoptotic and autophagy-dependent signaling pathways, but crucial pathways other subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis lysosome-dependent (LCD) cancer. Moreover, further discuss current situation several improve cancer treatment, such single-target, dual or multiple-target compounds, drug combinations, some new strategies would together shed light future directions attack vulnerabilities drugs for purposes.

Language: Английский

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Targeting ferroptosis opens new avenues for the development of novel therapeutics

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 21, 2023

Abstract Ferroptosis is an iron-dependent form of regulated cell death with distinct characteristics, including altered iron homeostasis, reduced defense against oxidative stress, and abnormal lipid peroxidation. Recent studies have provided compelling evidence supporting the notion that ferroptosis plays a key pathogenic role in many diseases such as various cancer types, neurodegenerative disease, involving tissue and/or organ injury, inflammatory infectious diseases. Although precise regulatory networks underlie are largely unknown, particularly respect to initiation progression diseases, recognized bona fide target for further development treatment prevention strategies. Over past decade, considerable progress has been made developing pharmacological agonists antagonists these ferroptosis-related conditions. Here, we provide detailed overview our current knowledge regarding ferroptosis, its pathological roles, regulation during disease progression. Focusing on use chemical tools preclinical studies, also summarize recent advances targeting across growing spectrum ferroptosis-associated Finally, discuss new challenges opportunities potential strategy treating

Language: Английский

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Interaction between macrophages and ferroptosis

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(4)

Published: April 16, 2022

Abstract Ferroptosis, a newly discovered iron-dependent cell death pathway, is characterized by lipid peroxidation and GSH depletion mediated iron metabolism morphologically, biologically genetically different from other programmed deaths. Besides, ferroptosis usually found accompanied inflammatory reactions. So far, it has been participating in the development of many kinds diseases. Macrophages are group immune cells that widely exist our body for host defense play an important role tissue homeostasis mediating inflammation regulating iron, amino acid metabolisms through their unique functions like phagocytosis efferocytosis, cytokines secretion ROS production under polarization. According to these common points characteristics macrophages functions, it’s obvious there must be relationship between ferroptosis. Therefore, review aims at revealing interaction concerning three integrating application certain curing diseases, mostly cancer. Finally, we also provide inspirations further studies therapy some diseases targeting resident distinct tissues regulate Facts Ferroptosis considered as form its nonapoptotic hydroperoxide, metabolisms. playing crucial part various including hepatic neurological cancer, etc. phagocytic cells, existing owning such production. proved participate initiating reactions maintain balance body. Recent try treat cancer altering macrophages’ polarization which damages tumor microenvironment induces cells. Open questions How do specifically? Can use treating than cancer? What can related macrophages? Is more effective therapies when diseases?

Language: Английский

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System Xc−/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy

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

Published: Aug. 29, 2022

The activation of ferroptosis is a new effective way to treat drug-resistant solid tumors. Ferroptosis an iron-mediated form cell death caused by the accumulation lipid peroxides. intracellular imbalance between oxidant and antioxidant due abnormal expression multiple redox active enzymes will promote produce reactive oxygen species (ROS). So far, few pathways regulators have been discovered regulate ferroptosis. In particular, cystine/glutamate antiporter (System X c − ), glutathione peroxidase 4 (GPX4) (GSH) /GSH/GPX4 axis) plays key role in preventing peroxidation-mediated ferroptosis, because which could be inhibited blocking System axis. This review aims present current understanding mechanism based on axis treatment

Language: Английский

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SLC7A11 regulated by NRF2 modulates esophageal squamous cell carcinoma radiosensitivity by inhibiting ferroptosis

Journal of Translational Medicine, Journal Year: 2021, Volume and Issue: 19(1)

Published: Aug. 26, 2021

Abstract Background Solute carrier family 7 member 11(SLC7A11) is a component of cysteine/glutamate transporter, which plays key role in tumor growth; however, its underlying effect on radiosensitivity esophageal squamous cell carcinoma (ESCC) remains unclear. This study aimed to clarify SLC7A11’s expression and correlation with nuclear factor erythroid-2 ( NRF2)-associated radioresistance ESCC. Methods We included 127 ESCC patients who received radical chemoradiotherapy. Immunohistochemical staining was used detect SLC7A11 NRF2 expression, the relationship between clinicopathological characteristics survival rates or therapy response were evaluated. Western blot, dual-reporter assays Chromatin immunoprecipitation (ChIP)-sequencing analyze their vitro. Their roles then investigated through multiple validation steps. Results overexpressed tissues positively correlated one another. significantly associated length, lymph node metastasis, TNM stage, while metastasis. Patients high had shorter overall progression-free survival, poor treatment response. The multivariate model showed that sex location are independent prognostic factors. In vitro analysis confirmed hyperactivation induced by directly binding promoter region, promoting radioresistance, reducing radiotherapy-induced lipid peroxidation levels, PTGS2 radiotherapy-related ferroptosis morphologic features. Conclusion Our reveals connection related worse poorer outcomes. SLC7A11-mediated inhibition NRF2-associated highlighting potential NRF2/SLC7A11/ferroptosis axis as future therapeutic targets against resistance biomarker.

Language: Английский

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Maresin1 Protect Against Ferroptosis-Induced Liver Injury Through ROS Inhibition and Nrf2/HO-1/GPX4 Activation

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

Published: April 4, 2022

Drugs, viruses, and chemical poisons stimulating live in a short period of time can cause acute liver injury (ALI). ALI further develop into serious diseases such as cirrhosis cancer. Therefore, how to effectively prevent treat has become the focus research. Numerous studies have reported Maresin1 (MaR1) anti-inflammatory effect protective functions on organs. In present study, we used d-galactosamine/lipopolysaccharide (D-GalN/LPS) establish an model, explored mechanism cells death caused by D-GalN/LPS, determined MaR1 D-GalN/LPS-induced ALI. vivo experiments, found that ferrostatin-1 significantly alleviated ALI, reduced serum alanine transaminase aspartate levels, improved survival rate mice. Meanwhile, inhibited hepatocyte death, tissue reactive oxygen species (ROS) expression, malondialdehyde (MDA), glutathione (GSH), GSH/oxidized (GSSG), iron content induced D-GalN/LPS addition, ferroptosis-induced through inhibiting release interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6. Subsequently, western blot showed expression nuclear factor E2-related 2(Nrf2)/heme oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4). vitro LPS-induced erastin-induced cell viability reduction. increased MDA GSH levels cells. Western level Nrf2/HO-1/GPX4. Next, Nrf2 was knocked down HepG2 cells, results decreased. Finally, flow cytometry revealed ROS production apoptosis. Overall, our study Nrf2/HO-1/GPX4 activation.

Language: Английский

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Targeting ferroptosis in acute kidney injury

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(2)

Published: Feb. 24, 2022

Acute kidney injury (AKI) is a major public health problem with high incidence and mortality. As form of programmed cell death (PCD), ferroptosis could be considered as process iron accumulation enhanced lipid peroxidation. Recently, the fundamental roles in AKI have attracted much attention. The network mechanism its to chronic disease (CKD) transition complicated multifactorial. Strategies targeting show great potential. Here, we review research progress on participation AKI. We hope that this work will provide clues for further studies

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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Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: June 21, 2023

Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct advantages of excellent safety and tolerability profile high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals metformin reduces risk cancer decreases cancer-related mortality in patients with diabetes; however, exact mechanisms are not well understood. Energy metabolism may be central to mechanism action. Based on altering whole-body energy or cellular state, metformin's modes action can divided into two broad, non-mutually exclusive categories: "direct effects", which induce direct effect cells, independent blood glucose insulin levels, "indirect effects" arise from systemic metabolic changes depending levels. In this review, we summarize updated account current knowledge antitumor action, elaborate underlying terms hallmarks cancer, propose potential applications repurposing therapeutics.

Language: Английский

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Non-coding RNAs and ferroptosis: potential implications for cancer therapy

Cell Death and Differentiation, Journal Year: 2022, Volume and Issue: 29(6), P. 1094 - 1106

Published: April 14, 2022

Abstract Ferroptosis is a recently defined form of regulated cell death, which biochemically and morphologically distinct from traditional forms programmed death such as apoptosis or necrosis. It driven by iron, reactive oxygen species, phospholipids that are oxidatively damaged, ultimately resulting in mitochondrial damage breakdown membrane integrity. Numerous cellular signaling pathways molecules involved the regulation ferroptosis, including enzymes control redox status. Alterations ferroptosis-regulating network can contribute to development various diseases, cancer. Evidence suggests ferroptosis commonly suppressed cancer cells, allowing them survive progress. However, cells resistant common chemotherapeutic drugs seem be highly susceptible inducers, highlighting great potential pharmacologic modulation for treatment. Non-coding RNAs (ncRNAs) considered master regulators processes, particularly where they have been implicated all hallmarks Recent work also demonstrated their involvement molecular ferroptosis. Hence, ncRNA-based therapeutics represent an exciting alternative modulate therapy. This review summarizes ncRNAs highlights underlying mechanisms light therapeutic applications.

Language: Английский

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