Targeting p53 pathways: mechanisms, structures and advances in therapy

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Март 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.

Язык: Английский

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p53 signaling in cancer progression and therapy

Cancer Cell International, Год журнала: 2021, Номер 21(1)

Опубликована: Дек. 1, 2021

Abstract The p53 protein is a transcription factor known as the "guardian of genome" because its critical function in preserving genomic integrity. TP53 gene mutated approximately half all human malignancies, including those breast, colon, lung, liver, prostate, bladder, and skin. When DNA damage occurs, on chromosome 17 stops cell cycle. If mutated, cycle unrestricted damaged replicated, resulting uncontrolled proliferation cancer tumours. Tumor-associated mutations are usually associated with phenotypes distinct from caused by loss tumor-suppressing exerted wild-type p53protein. Many these mutant proteins have oncogenic characteristics, therefore modulate ability cells to proliferate, escape apoptosis, invade metastasize. Because deficiency so common cancer, this an excellent option for treatment. In review, we will discuss some molecular pathways which might perform their activities, well prospective treatment methods based restoring tumor suppressive functions.

Язык: Английский

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Ferroptosis, radiotherapy, and combination therapeutic strategies

Protein & Cell, Год журнала: 2021, Номер 12(11), С. 836 - 857

Опубликована: Апрель 23, 2021

Ferroptosis, an iron-dependent form of regulated cell death driven by peroxidative damages polyunsaturated-fatty-acid-containing phospholipids in cellular membranes, has recently been revealed to play important role radiotherapy-induced and tumor suppression, mediate the synergy between radiotherapy immunotherapy. In this review, we summarize known as well putative mechanisms underlying crosstalk ferroptosis, discuss interactions ferroptosis other forms induced radiotherapy, explore combination therapeutic strategies targeting This review will provide frameworks for future investigations cancer therapy.

Язык: Английский

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Targeting cellular senescence with senotherapeutics: senolytics and senomorphics

FEBS Journal, Год журнала: 2022, Номер 290(5), С. 1362 - 1383

Опубликована: Янв. 11, 2022

The concept of geroscience is that since ageing the greatest risk factor for many diseases and conditions, targeting process itself will have impact on human health. Of hallmarks ageing, cellular senescence has emerged as a druggable therapeutic target extending healthspan in model organisms. Cellular cell state irreversible proliferative arrest driven by different types stress, including oncogene‐induced stress. Many senescent cells (SnCs) develop senescent‐associated secretory phenotype (SASP) comprising pro‐inflammatory cytokines, chemokines, proteases, bioactive lipids, inhibitory molecules, extracellular vesicles, metabolites, lipids other factors, able to promote chronic inflammation tissue dysfunction. SnCs up‐regulate anti‐apoptotic pathways (SCAPs) prevent them from dying despite accumulation damage DNA organelles. These SCAPs altered represent targets development senotherapeutic drugs induce selective death SnCs, specifically termed senolytics or suppress markers senescence, particular SASP, senomorphics. Here, we review current senomorphics treatment age‐related disorders extension healthy longevity. In addition, challenges documenting senolytic senomorphic activity pre‐clinical models clinical application senotherapeutics be discussed.

Язык: Английский

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The landscape of aging

Science China Life Sciences, Год журнала: 2022, Номер 65(12), С. 2354 - 2454

Опубликована: Сен. 2, 2022

Язык: Английский

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ROS: Basic Concepts, Sources, Cellular Signaling, and its Implications in Aging Pathways

Oxidative Medicine and Cellular Longevity, Год журнала: 2022, Номер 2022, С. 1 - 23

Опубликована: Окт. 19, 2022

Reactive oxygen species (ROS) are bioproducts of cellular metabolism. There is a range molecules with oxidizing properties known as ROS. Despite those being implied negatively in aging and numerous diseases, their key role signaling evident. ROS control several biological processes such inflammation, proliferation, cell death. The redox underlying these events one characteristic the new generation scientists aimed at defining environment. potential, which includes balance sources antioxidant system, implies an important target for understanding cells’ fate derived from signaling. In this review, we summarized chemical, balance, signaling, implications aging.

Язык: Английский

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The interplay between apoptosis and cellular senescence: Bcl-2 family proteins as targets for cancer therapy

Pharmacology & Therapeutics, Год журнала: 2021, Номер 230, С. 107943 - 107943

Опубликована: Июнь 26, 2021

Язык: Английский

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Protective Effects of Curcumin in Cardiovascular Diseases—Impact on Oxidative Stress and Mitochondria

Cells, Год журнала: 2022, Номер 11(3), С. 342 - 342

Опубликована: Янв. 20, 2022

Cardiovascular diseases (CVDs) contribute to a large part of worldwide mortality. Similarly, two the major risk factors for these diseases, aging and obesity, are also global problems. Aging, gradual decline body functions, is non-modifiable. Obesity, modifiable factor CVDs, predisposes type 2 diabetes mellitus (T2DM). Moreover, it affects not only vasculature heart but specific fat depots, which themselves have impact on development progression CVDs. Common denominators aging, T2DM include oxidative stress, mitochondrial dysfunction, metabolic abnormalities such as altered lipid profiles glucose metabolism, inflammation. Several plant substances curcumin, active compound in turmeric root, been used long time traditional medicine treatment Newer mechanistic, animal, human studies provide evidence that curcumin has pleiotropic effects attenuates numerous parameters an increased CVDs well obesity. Thus, nutraceutical could hold promise prevention more standardized clinical trials required fully unravel its potential.

Язык: Английский

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Role of p53 in breast cancer progression: An insight into p53 targeted therapy

Theranostics, Год журнала: 2023, Номер 13(4), С. 1421 - 1442

Опубликована: Янв. 1, 2023

The transcription factor p53 is an important regulator of a multitude cellular processes.In the presence genotoxic stress, activated to facilitate DNA repair, cell cycle arrest, and apoptosis.In breast cancer, tumor suppressive activities are frequently inactivated by either overexpression its negative MDM2, or mutation which present in 30-35% all cancer cases.Notably, frequency highly subtype dependent cancers, with majority hormone receptor-positive luminal subtypes retaining wild-type status while receptor-negative patients predominantly carry mutations gain-of-function oncogenic that contribute poorer prognosis.Thus, two-pronged strategy targeting mutant different can have clinical relevance.The development p53-based therapies has rapidly progressed recent years, include unique small molecule chemical inhibitors, stapled peptides, PROTACs, as well several genetic-based approaches using vectors engineered antibodies.In this review, we highlight therapeutic strategies pre-clinical overcome inactivation both p53-bearing tumors, discuss their efficacies limitations settings.

Язык: Английский

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GDF15, an emerging key player in human aging

Ageing Research Reviews, Год журнала: 2022, Номер 75, С. 101569 - 101569

Опубликована: Янв. 19, 2022

Язык: Английский

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