Cyclin-dependent kinases in DNA damage response

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2022, Номер 1877(3), С. 188716 - 188716

Опубликована: Март 7, 2022

The cyclin-dependent kinase (CDK) family plays a critical role in variety of signaling pathways that regulate transcription and cell-cycle progression. Recently, the CDKs DNA damage response (DDR) has emerged. affect both repair, contributing to fidelity cell division process as well maintenance genomic integrity following damage. This is due modulatory on double-strand break repair (DSBR) components, including their influence enzymes involved homologous recombination (HR) non-homologous end-joining (NHEJ). In this review, impact DDR discussed.

Язык: Английский

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Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Ноя. 28, 2023

The advent of iPSCs has brought about a significant transformation in stem cell research, opening up promising avenues for advancing cancer treatment. formation is multifaceted process influenced by genetic, epigenetic, and environmental factors. offer distinctive platform investigating the origin cancer, paving way novel approaches to treatment, drug testing, tailored medical interventions. This review article will provide an overview science behind iPSCs, current limitations challenges iPSC-based therapy, ethical social implications, comparative analysis with other types also discuss applications tumorigenesis, future tumorigenesis highlight successful case studies utilizing research. conclusion summarize advancements made research importance continued investment iPSC unlock full potential these cells.

Язык: Английский

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β-Sitosterol as a Promising Anticancer Agent for Chemoprevention and Chemotherapy: Mechanisms of Action and Future Prospects

Advances in Nutrition, Год журнала: 2023, Номер 14(5), С. 1085 - 1110

Опубликована: Май 27, 2023

Cancer is one of the primary causes death worldwide, and its incidence continues to increase yearly. Despite significant advances in research, search for effective nontoxic preventive therapeutic agents remains greatly important. a multimodal disease, where various mechanisms play roles occurrence progression. This highlights need multitargeted approaches that are not only safe inexpensive but also provide alternatives current regimens. β-Sitosterol (SIT), most abundant phytosterol found plant foods, represents such an option. Preclinical evidence over past few decades has overwhelmingly shown SIT exhibits multiple anticancer activities against varied cancers, as liver, cervical, colon, stomach, breast, lung, pancreatic, prostate addition leukemia, myeloma, melanoma, fibrosarcoma. In this article, we present latest perspectives on SIT-systematically summarizing antitumor action into 7 main sections combining challenges prospects-for use promising agent cancer prevention treatment. particular, plays role treatment mainly by enhancing apoptosis, inducing cell cycle arrest, bidirectionally regulating oxidative stress, improving metabolic reprogramming, inhibiting invasion metastasis, modulating immunity inflammation, combating drug resistance. Although holds great promise, poor aqueous solubility bioavailability coupled with low targeting efficacy limit clinical application. Further research novel delivery systems may improve these deficiencies. Overall, through complex pleiotropic mechanisms, good potential tumor chemoprevention chemotherapy. However, no trials have yet proven potential. review provides theoretical basis rationality further design conduct confirm activity SIT.

Язык: Английский

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A new wave of innovations within the DNA damage response

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

Опубликована: Сен. 8, 2023

Genome instability has been identified as one of the enabling hallmarks in cancer. DNA damage response (DDR) network is responsible for maintenance genome integrity cells. As cancer cells frequently carry DDR gene deficiencies or suffer from replicative stress, targeting processes could induce excessive damages (or unrepaired DNA) that eventually lead to cell death. Poly (ADP-ribose) polymerase (PARP) inhibitors have brought impressive benefit patients with breast (BRCA) mutation homologous recombination deficiency (HRD), which proves concept synthetic lethality treatment. Moreover, other two scenarios inhibitor application, replication stress and combination chemo- radio- therapy, are under active clinical exploration. In this review, we revisited progress therapy beyond launched first-generation PARP inhibitors. Next generation PARP1 selective inhibitors, maintain efficacy while mitigating side effects, may diversify application clinic. Albeit unavoidable on-mechanism toxicities, several small molecules checkpoints (gatekeepers) shown great promise preliminary results, warrant further evaluations. addition, repair pathways (caretakers) also preclinical development. With these progresses efforts, envision a new wave innovations within come age.

Язык: Английский

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The CDK inhibitor AT7519 inhibits human glioblastoma cell growth by inducing apoptosis, pyroptosis and cell cycle arrest

Cell Death and Disease, Год журнала: 2023, Номер 14(1)

Опубликована: Янв. 9, 2023

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor with a poor median survival of less than 15 months. However, clinical strategies and effective therapies are limited. Here, we found that second-generation small molecule multi-CDK inhibitor AT7519 potential drug for GBM treatment according to high-throughput screening via Approved Drug Library Clinical Compound (2718 compounds). We significantly inhibited cell viability proliferation U87MG, U251, patient-derived cells in dose-dependent manner. Furthermore, also phosphorylation CDK1/2 arrested cycle at G1-S G2-M phases. More importantly, induced intrinsic apoptosis pyroptosis caspase-3-mediated cleavage gasdermin E (GSDME). In glioblastoma intracranial subcutaneous xenograft assays, volume was reduced after AT7519. summary, induces death through multiple pathways inhibits growth, indicating chemical available treatment.

Язык: Английский

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pH-sensitive ameliorated quercetin delivery using graphene oxide nanocarriers coated with potential anticancer gelatin-polyvinylpyrrolidone nanoemulsion with bitter almond oil

Journal of Drug Delivery Science and Technology, Год журнала: 2023, Номер 82, С. 104339 - 104339

Опубликована: Март 10, 2023

The rapid rise of cancer worldwide demonstrates the importance treatment strategies. In addition to reduce side effects conventional treatments, targeted drug delivery systems increase performance and effectiveness. this research, nanocarriers comprising gelatin (G)-polyvinylpyrrolidone (PVP) coated graphene oxide (GO) were prepared for first time. nanocarries loaded with quercetin (QC) a dual nanoemulsion water/oil/water bitter almond oil was developed as membrane around nanocomposite control further release. XRD, FTIR, FESEM, DLS analysis confirmed success synthesis loading. resulting pH-sensitive system showed an 87.5% encapsulation efficiency 45% loading, which are among highest values reported up date. zeta potential nanocomposites about −40 mV, indicating good stability. release kinetics followed Higuchi model, presence resulted in better entrapping efficiency, controlled long-term MTT assay flow cytometry methods revealed rate cell death 53.14%, 36.51% apoptotic phase. Taking into account results obtained herein, PVP-G-GO-QC can be considered new promising treatment.

Язык: Английский

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CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence

Molecular Cell, Год журнала: 2023, Номер 83(22), С. 4062 - 4077.e5

Опубликована: Ноя. 1, 2023

Abnormal increases in cell size are associated with senescence and cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the remain unknown. We address this question using CDK4/6 inhibitors, arrest G0/G1 licensed treat advanced HR+/HER2- breast cancer. demonstrate that CDK4/6-inhibited overgrow during G0/G1, causing p38/p53/p21-dependent withdrawal. Cell withdrawal is triggered biphasic p21 induction. first wave caused osmotic stress, leading p38- size-dependent accumulation of p21. inhibitor washout results some entering S-phase. Overgrown experience replication resulting a second promotes G2 or subsequent G1. propose levels integrate signals overgrowth-triggered stresses determine fate. This model explains how hypertrophy can drive why inhibitors have long-lasting effects patients.

Язык: Английский

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Functional Nucleic Acids-Engineered Bio-Barcode Nanoplatforms for Targeted Synergistic Therapy of Multidrug-Resistant Cancer

ACS Nano, Год журнала: 2023, Номер 17(14), С. 13533 - 13544

Опубликована: Июль 17, 2023

Rational design of multifunctional nanomedicines has revolutionized the therapeutic efficacy cancers. Herein, we have constructed functional nucleic acids (FNAs)-engineered nanoplatforms based on concept a bio-barcode (BBC) for synergistic targeted therapy multidrug-resistant (MDR) cancer. In this study, platinum(IV) prodrug is synthesized to covalently link two kinds FNAs at rational ratio fabricate three-dimensional BBC-like DNA nanoscaffolds, accompanied by one-pot encapsulation ZnO nanoparticles (NPs) through electrostatic interaction. The multivalent AS1411 aptamers equipped in ZnO@BBCs facilitate specific and efficient endocytosis into MDR human lung adenocarcinoma cells (A549/DDP). response intracellular environment A549/DDP cells, such as lysosome-acidic pH overexpressed GSH, NPs are degraded Zn2+ ions generating reactive oxygen species (ROS), while Pt(IV) prodrugs reduced Pt(II) active glutathione (GSH), followed release DNAzymes chemotherapy gene therapy. particular, designed system plays an important role remodeling reverse cancer MDR. On one hand, depletion GSH promotes downregulation peroxidase 4 (GPX4) amplifying oxidative stress increasing lipid peroxidation (LPO), resulting activation ferroptosis. other silence early growth protein 1 (Egr-1) mRNA Zn2+-dependent directly inhibits proliferation migration which further suppresses P-glycoprotein (P-gp)-mediated drug efflux. Thus, proposed show great promise development versatile tools personalized

Язык: Английский

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The two sides of chromosomal instability: drivers and brakes in cancer

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Март 29, 2024

Abstract Chromosomal instability (CIN) is a hallmark of cancer and associated with tumor cell malignancy. CIN triggers chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes chromosomes. arises errors DNA replication segregation during division, formation abnormal and/or structure Errors result licensing as well stress, such double-strand breaks stalled forks; meanwhile, stem defects machinery, centrosome amplification, erroneous microtubule–kinetochore attachments, spindle assembly checkpoint, defective sister chromatids cohesion. In cells, deleterious damage, proteotoxic metabolic alteration, cycle arrest, senescence. Paradoxically, despite these negative consequences, one hallmarks found over 90% solid tumors blood cancers. Furthermore, could endow enhanced adaptation capabilities due increased intratumor heterogeneity, thereby facilitating adaptive resistance therapies; however, excessive induce death, “just-right” model for tumors. Elucidating complex nature crucial understanding dynamics tumorigenesis developing effective anti-tumor treatments. This review provides an overview causes consequences CIN, paradox phenomenon that continues perplex researchers. Finally, this explores potential CIN-based therapy.

Язык: Английский

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Protein neddylation and its role in health and diseases

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Апрель 4, 2024

Abstract NEDD8 (Neural precursor cell expressed developmentally downregulated protein 8) is an ubiquitin-like that covalently attached to a lysine residue of substrate through process known as neddylation, catalyzed by the enzyme cascade, namely activating (E1), conjugating (E2), and ligase (E3). The substrates neddylation are categorized into cullins non-cullin proteins. Neddylation activates CRLs (cullin RING ligases), largest family E3 ligases, whereas alters their stability activity, well subcellular localization. Significantly, pathway and/or many abnormally activated or over-expressed in various human diseases, such metabolic disorders, liver dysfunction, neurodegenerative cancers, among others. Thus, targeting becomes attractive strategy for treatment these diseases. In this review, we first provide general introduction on its biochemical regulation, crystal structures enzymes complex with cullin substrates; then discuss how governs key biological processes via modification substrates. We further review literature data dysregulated several particularly cancer, followed outline current efforts discovery small molecule inhibitors promising therapeutic approach. Finally, few perspectives were proposed extensive future investigations.

Язык: Английский

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