Copper induces cell death by targeting lipoylated TCA cycle proteins

Science, Journal Year: 2022, Volume and Issue: 375(6586), P. 1254 - 1261

Published: March 17, 2022

Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, unknown. Here, we show in human cells that copper-dependent, regulated death distinct from known mechanisms dependent on mitochondrial respiration. We copper-dependent occurs means of direct binding to lipoylated components the tricarboxylic acid (TCA) cycle. This results protein aggregation subsequent iron-sulfur cluster loss, which leads proteotoxic stress ultimately death. These findings may explain need ancient

Language: Английский

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Broadening horizons: the role of ferroptosis in cancer

Nature Reviews Clinical Oncology, Journal Year: 2021, Volume and Issue: 18(5), P. 280 - 296

Published: Jan. 29, 2021

Language: Английский

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Necroptosis, pyroptosis and apoptosis: an intricate game of cell death

Cellular and Molecular Immunology, Journal Year: 2021, Volume and Issue: 18(5), P. 1106 - 1121

Published: March 30, 2021

Abstract Cell death is a fundamental physiological process in all living organisms. Its roles extend from embryonic development, organ maintenance, and aging to the coordination of immune responses autoimmunity. In recent years, our understanding mechanisms orchestrating cellular its consequences on immunity homeostasis has increased substantially. Different modalities what become known as ‘programmed cell death’ have been described, some key players these processes identified. We learned more about intricacies that fine tune activity common ultimately shape different types death. These studies highlighted complex tipping balance between fates. Here, we summarize latest discoveries three most well understood death, namely, apoptosis, necroptosis, pyroptosis, highlighting unique pathways their effect surrounding cells organism whole.

Language: Английский

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Unlocking the potential of antibody–drug conjugates for cancer therapy

Nature Reviews Clinical Oncology, Journal Year: 2021, Volume and Issue: 18(6), P. 327 - 344

Published: Feb. 8, 2021

Language: Английский

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Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy

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

Published: June 20, 2022

Abstract In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led to unprecedented breakthroughs in cancer treatment. However, the fact that many tumors respond poorly or even not ICIs, partly caused absence of tumor-infiltrating lymphocytes (TILs), significantly limits application ICIs. Converting these “cold” into “hot” may ICIs is an unsolved question immunotherapy. Since it a general characteristic cancers resist apoptosis, induction non-apoptotic regulated cell death (RCD) emerging as new treatment strategy. Recently, several studies have revealed interaction between RCD and antitumor immunity. Specifically, autophagy, ferroptosis, pyroptosis, necroptosis exhibit synergistic responses while possibly exerting inhibitory effects on responses. Thus, targeted therapies (inducers inhibitors) against combination with exert potent activity, resistant This review summarizes multilevel relationship immunity RCD, including necroptosis, potential targeting improve efficacy malignancy.

Language: Английский

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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 cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Dec. 8, 2022

Abstract Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various activities, including clearance aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target development cancer medications recent years. However, because tumor show avoidance apoptosis, which causes treatment resistance recurrence, numerous studies been devoted alternative mortality processes, namely necroptosis, pyroptosis, ferroptosis, cuproptosis; these modalities extensively studied shown be crucial therapy effectiveness. Furthermore, evidence suggests that undergoing may alter immunogenicity microenvironment (TME) some extent, rendering it more suitable inhibiting progression metastasis. In addition, other components TME undergo abovementioned forms induce immune attacks on cells, resulting enhanced antitumor responses. Hence, this review discusses molecular processes features cuproptosis effects novel proliferation Importantly, introduces complex affect biology. It also summarizes potential agents nanoparticles or inhibit their therapeutic based from vivo vitro reports clinical trials inducers evaluated treatments patients. Lastly, we summarized impact modulating drug advantages adding modulators over conventional treatments.

Language: Английский

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The role of BCL-2 family proteins in regulating apoptosis and cancer therapy

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: Oct. 12, 2022

Apoptosis, as a very important biological process, is response to developmental cues or cellular stress. Impaired apoptosis plays central role in the development of cancer and also reduces efficacy traditional cytotoxic therapies. Members B-cell lymphoma 2 (BCL-2) protein family have pro- anti-apoptotic activities been studied intensively over past decade for their importance regulating apoptosis, tumorigenesis, responses anticancer therapy. Since inflammatory induced by apoptosis-induced cell death small, at present, drugs targeting has attracted more attention. Consequently, focus this review summarize current research on BCL-2 proteins proteins. Additionally, mechanism was explored. All findings indicate potential therapy cancer.

Language: Английский

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PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway?

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: March 24, 2022

Cancer is a severe public health issue that leading cause of mortality globally. It also an impediment to improving life expectancy worldwide. Furthermore, the global burden cancer incidence and death continuously growing. Current therapeutic options are insufficient for patients, tumor complexity heterogeneity necessitate customized medicine or targeted therapy. critical identify potential targets. Aberrant activation PI3K/AKT/mTOR pathway has significant role in carcinogenesis. This review summarized oncogenic PI3K/Akt/mTOR alterations various hallmarks associated with pathway, such as cell proliferation, autophagy, apoptosis, angiogenesis, epithelial-to-mesenchymal transition (EMT), chemoresistance. Importantly, this provided recent advances inhibitor research. Overall, in-depth understanding association between tumorigenesis development therapies targeting will help make clinical decisions.

Language: Английский

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Challenges and Opportunities in Cancer Drug Resistance

Chemical Reviews, Journal Year: 2020, Volume and Issue: 121(6), P. 3297 - 3351

Published: July 21, 2020

There has been huge progress in the discovery of targeted cancer therapies recent years. However, even for most successful and impactful drugs which have approved, both innate acquired mechanisms resistance are commonplace. These emerging studied intensively, enabled drug scientists to learn how it may be possible overcome such subsequent generations treatments. In some cases, novel candidates able supersede previously approved agents; other cases they used sequentially or combinations with existing This review summarizes current field terms challenges opportunities that presents scientists, a focus on small molecule therapeutics. As part this review, common themes approaches identified utilized successfully target resistance. includes increase potency selectivity, alternative chemical scaffolds, change mechanism action (covalents, PROTACs), increases blood-brain barrier permeability (BBBP), targeting allosteric pockets. Finally, wider covered as monoclonal antibodies (mAbs), bispecific antibodies, antibody conjugates (ADCs), combination therapies.

Language: Английский

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