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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Recent advances in targeted strategies for triple-negative breast cancer

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Aug. 28, 2023

Triple-negative breast cancer (TNBC), a highly aggressive subtype of cancer, negatively expresses estrogen receptor, progesterone and the human epidermal growth factor receptor 2 (HER2). Although chemotherapy is main form treatment for patients with TNBC, effectiveness TNBC still limited. The search more effective therapies urgent. Multiple targeted therapeutic strategies have emerged according to specific molecules signaling pathways expressed in TNBC. These include PI3K/AKT/mTOR inhibitors, Notch poly ADP-ribose polymerase antibody-drug conjugates. Moreover, immune checkpoint example, pembrolizumab, atezolizumab, durvalumab, are widely explored clinic. We summarize recent advances therapy immunotherapy aim serving as reference development individualized future.

Language: Английский

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Exploiting RIG-I-like receptor pathway for cancer immunotherapy

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Feb. 8, 2023

RIG-I-like receptors (RLRs) are intracellular pattern recognition that detect viral or bacterial infection and induce host innate immune responses. The RLRs family comprises retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated 5 (MDA5) laboratory of genetics physiology 2 (LGP2) have distinctive features. These not only recognize RNA intermediates from viruses bacteria, but also interact with endogenous such as the mislocalized mitochondrial RNA, aberrantly reactivated repetitive transposable elements in human genome. Evasion RLRs-mediated response may lead to sustained infection, defective immunity carcinogenesis. Therapeutic targeting provoke anti-infection effects, anticancer sensitize "immune-cold" tumors checkpoint blockade. In this review, we summarize current knowledge signaling discuss rationale for therapeutic cancer. We describe how can be activated by synthetic oncolytic viruses, mimicry radio-chemotherapy, agonists systemically delivered vivo. integration agonism interference CAR-T cells provides new dimensions complement cancer immunotherapy. Moreover, update progress recent clinical trials therapy involving activation modulation. Further studies mechanisms underlying will shed light on development therapeutics. Manipulation represents an opportunity clinically relevant therapy. Addressing challenges field help develop future generations

Language: Английский

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Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Oct. 14, 2024

Iron, an essential mineral in the body, is involved numerous physiological processes, making maintenance of iron homeostasis crucial for overall health. Both overload and deficiency can cause various disorders human diseases. Ferroptosis, a form cell death dependent on iron, characterized by extensive peroxidation lipids. Unlike other kinds classical unprogrammed death, ferroptosis primarily linked to disruptions metabolism, lipid peroxidation, antioxidant system imbalance. Ferroptosis regulated through transcription, translation, post-translational modifications, which affect cellular sensitivity ferroptosis. Over past decade or so, diseases have been as part their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous cardiovascular musculoskeletal Ferroptosis-related proteins become attractive targets many major that are currently incurable, some regulators shown therapeutic effects clinical trials although further validation potential needed. Therefore, in-depth analysis its molecular mechanisms may offer additional strategies prevention treatment. In this review, we discuss significance contribution etiology development along with evidence supporting targeting approach. Importantly, evaluate recent promising interventions, providing guidance future targeted treatment therapies against

Language: Английский

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Focal adhesion kinase: from biological functions to therapeutic strategies

Experimental Hematology and Oncology, Journal Year: 2023, Volume and Issue: 12(1)

Published: Sept. 25, 2023

Focal adhesion kinase (FAK), a nonreceptor cytoplasmic tyrosine kinase, is vital participant in primary cellular functions, such as proliferation, survival, migration, and invasion. In addition, FAK regulates cancer stem cell activities contributes to the formation of tumor microenvironment (TME). Importantly, increased expression activity are strongly associated with unfavorable clinical outcomes metastatic characteristics numerous tumors. vitro vivo studies have demonstrated that modulating by application inhibitors alone or combination treatment regimens could be effective for therapy. Based on these findings, several agents targeting been exploited diverse preclinical models. This article briefly describes structure function FAK, well research progress therapies. We also discuss challenges future directions regarding anti-FAK

Language: Английский

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Targeting the Warburg effect: A revisited perspective from molecular mechanisms to traditional and innovative therapeutic strategies in cancer

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 14(3), P. 953 - 1008

Published: Dec. 16, 2023

Cancer reprogramming is an important facilitator of cancer development and survival, with tumor cells exhibiting a preference for aerobic glycolysis beyond oxidative phosphorylation, even under sufficient oxygen supply condition. This metabolic alteration, known as the Warburg effect, serves significant indicator malignant transformation. The effect primarily impacts occurrence by influencing pathway in cells. Key enzymes involved this process include glucose transporters (GLUTs), HKs, PFKs, LDHs, PKM2. Moreover, expression transcriptional regulatory factors proteins, such FOXM1, p53, NF-

Language: Английский

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Ferroptosis: a novel regulated cell death participating in cellular stress response, radiotherapy, and immunotherapy

Experimental Hematology and Oncology, Journal Year: 2023, Volume and Issue: 12(1)

Published: July 27, 2023

Abstract Background Ferroptosis is a regulated cell death mode triggered by iron-dependent toxic membrane lipid peroxidation. As novel modality that morphologically and mechanistically different from other forms of death, such as apoptosis necrosis, ferroptosis has attracted extensive attention due to its association with various diseases. Evidence on potential therapeutic strategy accumulated the rapid growth research targeting for tumor suppression in recent years. Methods We summarize currently known characteristics major regulatory mechanisms present role cellular stress responses, including ER autophagy. Furthermore, we elucidate applications radiotherapy immunotherapy, which will be beneficial exploring new strategies clinical treatment. Result conclusion Based specific biomarkers precise patient-specific assessment, great translated into practical approaches cancer therapy, significantly contributing prevention, diagnosis, prognosis, treatment cancer.

Language: Английский

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2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: May 15, 2024

Abstract Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide + (NAD )-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed SIRT3 plays its critical roles cardiac fibrosis, myocardial fibrosis even heart failure (HF), through deacetylation modifications. Accordingly, discovery of activators elucidating their underlying mechanisms HF should be urgently needed. Herein, we identified new small-molecule activator (named 2-APQC) by structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced hypertrophy vitro vivo rat models. Importantly, knockout mice, could not relieve HF, suggesting dependent on for protective role. Mechanically, found inhibit mammalian target rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal (JNK) transforming growth factor-β (TGF-β)/ small mother against decapentaplegic (Smad3) pathways improve ISO-induced fibrosis. Based upon RNA-seq analyses, demonstrated SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis closely assoiated with HF. By activating PYCR1, enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated (p38MAPK) pathway thereby protecting mitochondrialoxidative damage. Moreover, activation facilitate AMP-activated (AMPK)-Parkin necrosis. Together, our results demonstrate targeted alleviates regulating homeostasis, which provide clue exploiting promising candidate future therapeutics.

Language: Английский

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Natural products and derivatives for breast cancer treatment: From drug discovery to molecular mechanism

Phytomedicine, Journal Year: 2024, Volume and Issue: 129, P. 155600 - 155600

Published: April 7, 2024

Breast cancer stands as the most common malignancy among women globally and a leading cause of cancer-related mortality. Conventional treatments, such surgery, hormone therapy, radiotherapy, chemotherapy, small-molecule targeted often fall short addressing complexity heterogeneity certain breast subtypes, to drug resistance metastatic progression. Thus, search for novel therapeutic targets agents is imperative. Given their low toxicity abundant variety, natural products derivatives are increasingly considered valuable sources anticancer drugs. This review aims elucidate pharmacological impacts underlying mechanisms active compounds found in select derivatives, primarily focusing on treatment. It intends underscore potential these substances combating guide future research directions development product-based therapeutics. We conducted comprehensive searches electronic databases PubMed, Web Science, Scopus until October 2023, using keywords 'breast cancer', 'natural products', 'derivatives', 'mechanism', 'signaling pathways', various keyword combinations. The presents spectrum phytochemicals, including but not limited flavonoids, polyphenols, alkaloids, examines actions animal cellular models cancer. effects manifested through diverse mechanisms, induction cell death via apoptosis autophagy, suppression tumor angiogenesis. An increasing array proving effective against Future strategies can benefit from strategic enhancement properties compounds, optimization action, improved bioavailability, minimized side effects. forthcoming should prioritize facets maximize

Language: Английский

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Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets

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

Published: Sept. 14, 2022

Abstract Regulated cell death (RCD) is a critical and active process that controlled by specific signal transduction pathways can be regulated genetic signals or drug interventions. Meanwhile, RCD closely related to the occurrence therapy of multiple human cancers. Generally, subroutines are key tumorigenesis, which contributed our better understanding cancer pathogenesis therapeutics. Indole alkaloids derived from natural sources well defined for their outstanding biological pharmacological properties, like vincristine, vinblastine, staurosporine, indirubin, 3,3′-diindolylmethane, currently used in clinic under clinical assessment. Moreover, such compounds play significant role discovering novel anticancer agents. Thus, here we systemically summarized recent advances indole as agents targeting different subroutines, including classical apoptosis autophagic signaling crucial other ferroptosis, mitotic catastrophe, necroptosis, anoikis, cancer. further discussed cross talk between mediated combined strategies (e.g., 3,10-dibromofascaplysin with olaparib) exhibit therapeutic potential against various cancers regulating subroutines. In short, information provided this review on regulation targets expected beneficial design molecules greater thereby facilitating development new therapy. Graphic abstract

Language: Английский

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