The molecular basis and disease relevance of non-homologous DNA end joining

Nature Reviews Molecular Cell Biology, Journal Year: 2020, Volume and Issue: 21(12), P. 765 - 781

Published: Oct. 19, 2020

Language: Английский

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cAMP Signaling in Cancer: A PKA-CREB and EPAC-Centric Approach

Cells, Journal Year: 2022, Volume and Issue: 11(13), P. 2020 - 2020

Published: June 24, 2022

Cancer is one of the most common causes death globally. Despite extensive research and considerable advances in cancer therapy, fundamentals disease remain unclear. Understanding key signaling mechanisms that cause cell malignancy may help to uncover new pharmaco-targets. Cyclic adenosine monophosphate (cAMP) regulates various biological functions, including those malignant cells. intracellular second messenger pathways crucial for identifying downstream proteins involved growth development. cAMP a variety physiological pathological activities. There be an impact on gene transcription from protein kinase A (PKA) as well its effectors, such response element-binding (CREB). The position CREB numerous implies oncogenic potential tumor Tumor associated with increased expression activation. PKA can used both onco-drug target biomarker find, identify, stage tumors. Exploring effectors their has become easier using exchange directly activated by (EPAC) modulators. This system inhibit or accelerate depending environment. As are critical development, targeting them useful treatment strategy. Moreover, reviewing material distinct viewpoint, this review aims give knowledge pathway related incidence These innovative insights seek encourage development novel techniques approaches.

Language: Английский

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H2AX: A key player in DNA damage response and a promising target for cancer therapy

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 175, P. 116663 - 116663

Published: April 30, 2024

Cancer is caused by a complex interaction of factors that interrupt the normal growth and division cells. At center this process intricate relationship between DNA damage cellular mechanisms responsible for maintaining genomic stability. When not repaired, it can cause genetic mutations contribute to initiation progression cancer. On other hand, response system, which involves phosphorylation histone variant H2AX (γH2AX), crucial in preserving integrity signaling facilitating repair double-strand breaks. This review provides an explanation molecular dynamics context response. It emphasizes role recruiting localizing machinery at sites chromatin damage. The explains how phosphorylation, facilitated master kinases ATM ATR, acts as signal damage, triggering downstream pathways govern cell cycle checkpoints, apoptosis, fate decision death. critical regulatory point, ensuring survival promoting or steering cells towards apoptosis cases catastrophic Moreover, we explore therapeutic potential targeting cancer treatment, leveraging its dual function biomarker target. By delineating lead roles control, highlight significance both prognostic tool focal point intervention, offering insights into utility enhancing efficacy treatments.

Language: Английский

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A DNA tetrahedron-based nanosuit for efficient delivery of amifostine and multi-organ radioprotection

Bioactive Materials, Journal Year: 2024, Volume and Issue: 39, P. 191 - 205

Published: May 21, 2024

Unnecessary exposure to ionizing radiation (IR) often causes acute and chronic oxidative damages normal cells organs, leading serious physiological even life-threatening consequences. Amifostine (AMF) is a validated radioprotectant extensively applied in chemotherapy medicine, but the short half-life limits its bioavailability clinical applications, remaining as great challenge be addressed. DNA-assembled nanostructures especially tetrahedral framework nucleic acids (tFNAs) are promising nanocarriers with preeminent biosafety, low biotoxicity, high transport efficiency. The tFNAs also have relative long-term maintenance for structural stability excellent endocytosis capacity. We therefore synthesized tFNA-based delivery system of AMF multi-organ radioprotection (tFNAs@AMF, termed nanosuit). By establishing mice models accidental total body irradiation (TBI) radiotherapy model Lewis lung cancer, we demonstrated that nanosuit could shield from IR-induced DNA damage by regulating molecular biomarkers anti-apoptosis anti-oxidative stress. In model, pretreated exhibited satisfactory alteration superoxide dismutase (SOD) activities malondialdehyde (MDA) contents, functional recovery hematopoietic system, reducing pathological safeguarding lethal radiation. More importantly, showed selective organs without interferences tumor control cancer. Based on conveniently available tetrahedron-based nanocarrier, this work presents high-efficiency prolonged enhanced multi-organs. Such pioneers strategy translation potential radioactivity protection.

Language: Английский

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Pro-oxidant Actions of Carotenoids in Triggering Apoptosis of Cancer Cells: A Review of Emerging Evidence

Antioxidants, Journal Year: 2020, Volume and Issue: 9(6), P. 532 - 532

Published: June 17, 2020

Carotenoids are well known for their potent antioxidant function in the cellular system. However, cancer cells with an innately high level of intracellular reactive oxygen species (ROS), carotenoids may act as pro-oxidant molecules and trigger ROS-mediated apoptosis. In recent years, several common dietary carotenoids, including astaxanthin, β-carotene, fucoxanthin, lycopene, has been investigated effective killing effects on various cell lines. Besides, when delivered ROS-inducing cytotoxic drugs (e.g., anthracyclines), they can minimize adverse these normal by acting antioxidants without interfering pro-oxidants. These dynamic actions optimize oxidative stress while enhancing cells. This review discusses possible mechanisms carotenoid-triggered ROS production cells, activation pro-apoptotic signaling ROS, apoptotic death. Moreover, synergistic anti-cancer discussed, research gaps suggested.

Language: Английский

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DNA-PKcs: A Multi-Faceted Player in DNA Damage Response

Frontiers in Genetics, Journal Year: 2020, Volume and Issue: 11

Published: Dec. 23, 2020

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a member of the phosphatidylinositol 3-kinase related family, which can phosphorylate more than 700 substrates. As core enzyme, DNA-PKcs forms active DNA-PK holoenzyme with Ku80/Ku70 heterodimer to play crucial roles in cellular DNA damage response (DDR). Once double strand breaks (DSBs) occur cells, promptly recruited into sites and activated. auto-phosphorylated phosphorylated by Ataxia-Telangiectasia Mutated at multiple sites, phosphorylates other targets, participating series DDR repair processes, determine cells' fates: DSBs NHEJ pathway choice, replication stress response, cell cycle checkpoints, telomeres length maintenance, senescence, autophagy, etc. Due special multi-faceted responses damage, it important precisely regulate formation dynamic its functional complex activities for guarding genomic stability. On hand, targeting has been considered as promising strategy exploring novel radiosensitizers killing agents cancer cells. Combining inhibitors radiotherapy effectively enhance efficacy radiotherapy, offering possibilities therapy.

Language: Английский

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Progress towards a clinically-successful ATR inhibitor for cancer therapy

Current Research in Pharmacology and Drug Discovery, Journal Year: 2021, Volume and Issue: 2, P. 100017 - 100017

Published: Jan. 1, 2021

The DNA damage response (DDR) is now known to play an important role in both cancer development and its treatment. Targeting proteins such as ATR (Ataxia telangiectasia mutated Rad3-related) kinase, a major regulator of DDR, has demonstrated significant therapeutic potential treatment, with inhibitors having shown anti-tumour activity not just monotherapies, but also potentiating the effects conventional chemotherapy, radiotherapy, immunotherapy. This review focuses on biology ATR, functional rationale behind inhibition this target approach, including evaluation progress current status potent specific that have emerged recent decades. applications these preclinical clinical studies either single agents or combinations radiotherapy immunotherapy are extensively discussed. concludes some insights into various concerns raised observed settings, suggested solutions.

Language: Английский

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Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Journal of Clinical Medicine, Journal Year: 2020, Volume and Issue: 9(9), P. 2934 - 2934

Published: Sept. 11, 2020

Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by excessive proliferation and accumulation of immature blasts in the bone marrow. AML has very poor 5-year survival rate just 16% UK; hence, more efficacious, tolerable, targeted therapy required. Persistent stem cell (LSC) populations underlie patient relapse development resistance to therapy. Identification critical oncogenic signaling pathways LSC may provide new avenues for novel therapeutic strategies. The phosphatidylinositol-3-kinase (PI3K)/Akt mammalian target rapamycin (mTOR) pathway, often hyperactivated AML, required sustain potential LSCs. Growing evidence suggests that targeting key components this pathway represent an effective treatment kill Despite this, accruing significant body scientific knowledge, PI3K/Akt/mTOR inhibitors have not translated into clinical practice. In article, we review laboratory-based role outcomes from current studies using inhibitors. Based on these results, discuss putative mechanisms inhibition, offering rationale candidate combination therapies incorporating precision medicine AML.

Language: Английский

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Overcoming PARPi resistance: Preclinical and clinical evidence in ovarian cancer

Drug Resistance Updates, Journal Year: 2021, Volume and Issue: 55, P. 100744 - 100744

Published: Jan. 18, 2021

Language: Английский

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Structural insights into inhibitor regulation of the DNA repair protein DNA-PKcs

Nature, Journal Year: 2022, Volume and Issue: 601(7894), P. 643 - 648

Published: Jan. 5, 2022

Abstract The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has a central role in non-homologous end joining, one of the two main pathways that detect and repair DNA double-strand breaks (DSBs) humans 1,2 . DNA-PKcs is great importance repairing pathological DSBs, making inhibitors attractive therapeutic agents for cancer combination with DSB-inducing radiotherapy chemotherapy 3 Many selective have been developed exhibit potential as treatment various cancers 4 Here we report cryo-electron microscopy (cryo-EM) structures human natively purified from HeLa cell nuclear extracts, complex adenosine-5′-(γ-thio)-triphosphate (ATPγS) four (wortmannin, NU7441, AZD7648 M3814), including drug candidates undergoing clinical trials. reveal molecular details ATP binding at active site before catalysis provide insights into modes action specificities competitive inhibitors. Of note, ligands causes movement PIKK regulatory domain (PRD), revealing connection between p-loop PRD conformations. Electrophoretic mobility shift assay cryo-EM studies on holoenzyme further show ligand does not negative allosteric or inhibitory effect assembly function through direct competition ATP. Overall, described this study should greatly assist future efforts rational design targeting DNA-PKcs, demonstrating structure-guided development large challenging targets.

Language: Английский

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