Targeting p53 pathways: mechanisms, structures and advances in therapy

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

Published: March 1, 2023

The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. p53 protein transcription factor that can activate expression multiple target genes plays critical roles regulating cell cycle, apoptosis, genomic stability, widely regarded as "guardian genome". Accumulating evidence shown also regulates metabolism, ferroptosis, microenvironment, autophagy so on, all which contribute to suppression. Mutations not only impair its function, but confer oncogenic properties mutants. Since mutated inactivated malignant tumors, it very attractive for developing new anti-cancer drugs. However, until recently, was considered an "undruggable" little progress made with p53-targeted therapies. Here, we provide systematic review diverse molecular mechanisms signaling pathway how mutations impact progression. We discuss key structural features inactivation by mutations. In addition, efforts have therapies, challenges encountered clinical development.

Language: Английский

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Modulating Nitric Oxide: Implications for Cytotoxicity and Cytoprotection

Antioxidants, Journal Year: 2024, Volume and Issue: 13(5), P. 504 - 504

Published: April 23, 2024

Despite the significant progress in fields of biology, physiology, molecular medicine, and pharmacology; designation properties nitrogen monoxide regulation life-supporting functions organism; numerous works devoted to this molecule, there are still many open questions field. It is widely accepted that nitric oxide (•NO) a unique molecule that, despite its extremely simple structure, has wide range body, including cardiovascular system, central nervous system (CNS), reproduction, endocrine respiration, digestion, etc. Here, we systematize •NO, contributing conditions physiological norms, as well various pathological processes, mechanisms cytoprotection cytodestruction. Current experimental clinical studies contradictory describing role •NO pathogenesis diseases CNS. We describe cytoprotective action associated with expression antiapoptotic chaperone proteins mitochondrial function. The most prominent cytodestruction—the initiation nitrosative oxidative stresses, production reactive oxygen species, participation apoptosis mitosis. formation endothelial dysfunction also considered. Moreover, focus on ways pharmacological modulation nitroxidergic allow for decrease cytodestructive increase ones.

Language: Английский

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Mismatch prime editing gRNA increased efficiency and reduced indels

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 2, 2025

Prime editing enables precise and efficient genome editing, but its efficacy is hindered by pegRNA's 3' extension, forming secondary structures due to high complementarity with the protospacer. The continuous presence of prime system also leads unintended indel formation, raising safety concerns for therapeutic applications. To address these challenges, we develop a mismatched pegRNA (mpegRNA) strategy that introduces bases into protospacer, reducing structure preventing sustained activity. Our findings show mpegRNA enhances efficiency up 2.3 times reduces levels 76.5% without compromising performance. Combining epegRNA further increases 14-fold, or 2.4-fold in PE4max/PE5max systems, underscoring potential research therapy. AlphaFold 3 analysis suggests optimal contributes significantly improved outcomes. Overall, advances technology, improving while indels. extension. Here authors reduce formation can increase

Language: Английский

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Resveratrol, Epigallocatechin Gallate and Curcumin for Cancer Therapy: Challenges from Their Pro-Apoptotic Properties

Life, Journal Year: 2023, Volume and Issue: 13(2), P. 261 - 261

Published: Jan. 17, 2023

Plant-derived bioactive compounds are gaining wide attention for their multiple health-promoting activities and in particular anti-cancer properties. Several studies have highlighted how they can prevent cancer initiation progression, improve the effectiveness of chemotherapy, and, some cases, limit side effects chemotherapy agents. In this paper, we provide an update literature on three extensively studied plant-derived compounds, namely resveratrol, epigallocatechin gallate, curcumin, with a special focus molecular mechanisms inducing apoptosis major types cancers globally.

Language: Английский

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Canonical and non-canonical functions of p53 isoforms: potentiating the complexity of tumor development and therapy resistance

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(6)

Published: June 12, 2024

Abstract Full-length p53 (p53α) plays a pivotal role in maintaining genomic integrity and preventing tumor development. Over the years, was found to exist various isoforms, which are generated through alternative splicing, initiation of translation, internal ribosome entry site. either C-terminally altered or N-terminally truncated, exhibit distinct biological roles compared p53α, have significant implications for development therapy resistance. Due lack part and/or complete C- N-terminal domains, ectopic expression some isoforms failed induce canonical transcriptional targets p53α like CDKN1A MDM2 , even though they may bind their promoters. Yet, Δ40p53α still activate subsets including BAX . Furthermore, certain transactivate novel p53α. More recently, non-canonical functions DNA repair different replication unrelated activities were discovered, amplifying potential as master regulator physiological suppressor human cells. Both regarding functions, frequently exert dominant negative effects on its partners, is modified by relative isoform levels. Underlying mechanisms include hetero-oligomerization, changes subcellular localization, aggregation. These processes ultimately influence net give rise diverse cellular outcomes. Biological cancer Dysregulated has been observed types associated with clinical In conclusion, expanded our understanding complex regulatory network involving tumors. Unraveling underlying provides new avenues studies aiming at better developing therapeutic interventions overcome

Language: Английский

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Roles of chromatin and genome instability in cellular senescence and their relevance to ageing and related diseases

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(12), P. 979 - 1000

Published: Oct. 3, 2024

Language: Английский

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PARP1 at the crossroad of cellular senescence and nucleolar processes

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 94, P. 102206 - 102206

Published: Jan. 24, 2024

Language: Английский

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Triple-Negative Breast Cancer Progression and Drug Resistance in the Context of Epithelial–Mesenchymal Transition

Cancers, Journal Year: 2025, Volume and Issue: 17(2), P. 228 - 228

Published: Jan. 12, 2025

Triple-negative breast cancer (TNBC) is one of the most difficult subtypes to treat due its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk metastasis, lower overall survival compared other subtypes. Despite advancements in targeted therapies, traditional chemotherapy (primarily using platinum compounds taxanes) continues be standard treatment for TNBC, often limited long-term efficacy. tumors are heterogeneous, displaying diverse mutation profile considerable chromosomal instability, which complicates therapeutic interventions. The development chemoresistance frequently associated process epithelial–mesenchymal transition (EMT), during epithelial tumor cells acquire mesenchymal-like phenotype. This shift enhances metastatic potential, while simultaneously reducing effectiveness chemotherapeutics. It has also been suggested that EMT plays central role stem cells. Hence, there growing interest exploring small-molecule inhibitors target as future strategy overcoming resistance improving outcomes patients TNBC. review focuses on progression drug emphasis these processes. We present TNBC-specific EMT-related features, key protein markers, various signaling pathways involved. discuss important mechanisms factors related within context EMT, highlighting improve patients’ outcomes.

Language: Английский

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Distinct characteristics of the DNA damage response in mammalian oocytes

Experimental & Molecular Medicine, Journal Year: 2024, Volume and Issue: 56(2), P. 319 - 328

Published: Feb. 14, 2024

Abstract DNA damage is a critical threat that poses significant challenges to all cells. To address this issue, cells have evolved sophisticated molecular and cellular process known as the response (DDR). Among various cell types, mammalian oocytes, which remain dormant in ovary for extended periods, are particularly susceptible damage. The occurrence of oocytes can result genetic abnormalities, potentially leading infertility, birth defects, even abortion. Therefore, understanding how detect repair paramount importance maintaining oocyte quality preserving fertility. Although fundamental concept DDR conserved across an emerging body evidence reveals striking distinctions between somatic In review, we highlight distinctive characteristics discuss clinical implications oocytes.

Language: Английский

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Anticancer Activity of Metallodrugs and Metallizing Host Defense Peptides—Current Developments in Structure-Activity Relationship

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 7314 - 7314

Published: July 3, 2024

This article provides an overview of the development, structure and activity various metal complexes with anti-cancer activity. Chemical researchers continue to work on development synthesis new molecules that could act as anti-tumor drugs achieve more favorable therapies. It is therefore important have information about chemotherapeutic substances their mode action. review focuses metallodrugs contain a key structural fragment, cisplatin paving way for application. The text also looks at ruthenium complexes, including therapeutic applications phosphorescent ruthenium(II) emphasizing dual role in therapy diagnostics. In addition, antitumor activities titanium gold derivatives, side effects, ongoing research improve efficacy reduce adverse effects are discussed. Metallization host defense peptides (HDPs) ions highlighted strategy significantly enhances anticancer by broadening mechanisms

Language: Английский

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