Assessing the antioxidant properties of Naringin and Rutin and investigating their oxidative DNA damage effects in breast cancer

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: July 3, 2024

Abstract This work examines the capacity of Naringin and Rutin to influence DNA damage response (DDR) pathway by investigating their interactions with key DDR proteins, including PARP-1, ATM, ATR, CHK1, WEE1. Through a combination in silico molecular docking vitro evaluations, we investigated cytotoxic genotoxic effects these compounds on MDA-MB-231 cells, comparing them normal human fibroblast cells (2DD) quiescent (QFC). The research found that had strong affinities for indicating specifically regulate pathways cancer cells. Both exhibited preferential cytotoxicity towards while preserving vitality 2DD as demonstrated experiments conducted at dose 10 µM. comet performed particularly QFC provide valuable information impact Rutin, highlighting targeted initiation need use precise cell models appropriately evaluate toxicity genotoxicity is emphasized this discrepancy. In addition, ADMET drug-likeness investigations have pharmacological potential compounds; however, they also pointed out necessity optimization improve therapeutic profiles. antioxidant capabilities were assessed using DPPH free radical scavenging assays concentration results confirmed both role reducing oxidative stress, hence enhancing anticancer effects. Overall, show medicines modulating treatment. They exhibit selective sparing possess properties. analysis enhances our understanding uses natural chemicals treatment, supporting more mechanisms action clinical effectiveness.

Language: Английский

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Olaparib-Resistant BRCA2MUT Ovarian Cancer Cells with Restored BRCA2 Abrogate Olaparib-Induced DNA Damage and G2/M Arrest Controlled by the ATR/CHK1 Pathway for Survival

Cells, Journal Year: 2023, Volume and Issue: 12(7), P. 1038 - 1038

Published: March 29, 2023

The PARP inhibitor (PARPi) olaparib is currently the drug of choice for serous ovarian cancer (OC), especially in patients with homologous recombination (HR) repair deficiency associated deleterious BRCA1/2 mutations. Unfortunately, OC who fail to respond PARPi or relapse after treatment have limited therapeutic options. To elucidate resistance and enhance efficacy olaparib, intracellular factors exploited by cells achieve decreased sensitivity were examined. An olaparib-resistant cell line, PEO1-OR, was established from BRCA2MUT PEO1 cells. anticancer activity action combined inhibitors ATR/CHK1 pathway (ceralasertib as ATRi, MK-8776 CHK1i) olaparib-sensitive -resistant lines evaluated. Whole-exome sequencing revealed that PEO1-OR acquire through subclonal enrichment BRCA2 secondary mutations restore functional full-length protein. Moreover, upregulate HR repair-promoting (BRCA1, BRCA2, RAD51) PARP1. Olaparib-inducible activation G2/M arrest abrogated Drug assays are less sensitive ATRi CHK1i agents. Combined effective considering inhibition metabolic activity, colony formation, survival, accumulation DNA double-strand breaks, chromosomal aberrations. However, synergistic antitumor between compounds achievable Collectively, display co-existing repair-related mechanisms confer which may be effectively utilized resensitize them via combination therapy. Importantly, addition has potential overcome acquired PARPi.

Language: Английский

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Advances in molecular targeted therapies to increase efficacy of (chemo)radiation therapy

Strahlentherapie und Onkologie, Journal Year: 2023, Volume and Issue: 199(12), P. 1091 - 1109

Published: April 11, 2023

Abstract Recent advances in understanding the tumor’s biology line with a constantly growing number of innovative technologies have prompted characterization patients’ individual malignancies and may display prerequisite to treat cancer at its patient tumor vulnerability. In recent decades, radiation- induced signaling promoting local events for radiation sensitization were explored detail, resulting development novel molecular targets. A multitude pharmacological, genetic, immunological principles, including small molecule- antibody-based targeted strategies, been developed that are suitable combined concepts (RT) or chemoradiation therapy (CRT). Despite plethora promising experimental preclinical findings, however, so far, only very limited clinical trials demonstrated better outcome and/or benefit when RT CRT agents. The current review aims summarize progress therapies targeting oncogenic drivers, DNA damage cell cycle response, apoptosis pathways, adhesion molecules, hypoxia, microenvironment impact refractoriness boost response. addition, we will discuss nanotechnology, e.g., RNA protein-degrading proteolysis-targeting chimeras (PROTACs) open new ways from molecular-targeted approaches improved efficacy.

Language: Английский

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Oryza glumaepatula and calcium oxide nanoparticles enhanced Cr stress tolerance by maintaining antioxidant defense, chlorophyll and gene expression levels in rice

Journal of Environmental Management, Journal Year: 2024, Volume and Issue: 368, P. 122239 - 122239

Published: Aug. 25, 2024

Language: Английский

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Ruthenium(II) Complex with 1-Hydroxy-9,10-Anthraquinone Inhibits Cell Cycle Progression at G0/G1 and Induces Apoptosis in Melanoma Cells

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(1), P. 63 - 63

Published: Jan. 8, 2025

Melanoma is the most aggressive and lethal skin cancer that affects thousands of people worldwide. Ruthenium complexes have shown promising results as chemotherapeutics, offering several advantages over platinum drugs, such potent efficacy, low toxicity, less drug resistance. Additionally, anthraquinone derivatives broad therapeutic applications, including melanoma. Thus, two new ruthenium with 1-hydroxy-9,10-anthraquinone were obtained: trans-[Ru(HQ)(PPh3)2(bipy)]PF6 (1) cis-[RuCl2(HQ)(dppb)] (2), where HQ = 1-hydroxy-9,10-anthraquinone, PPh3 triphenylphospine, bipy 2,2'-bipyridine, PF6 hexafluorophosphate, dppb 1,4-bis(diphenylphosphine)butane. The characterized by infrared (IR), UV-vis, 1H, 13C{1H}, 31P{1H} NMR spectroscopies, molar conductivity, cyclic voltammetry, elemental analysis. Furthermore, density functional theory (DFT) calculations performed. Compound (2) was determined single-crystal X-ray diffraction, which confirms bidentate coordination mode through carbonyl phenolate oxygens. DNA-binding experiments yielded constants 105 M-1 (Kb 6.93 × for 1.60 (2)) demonstrate both can interact DNA intercalation, electrostatic attraction, or hydrogen bonding. cytotoxicity profiles compounds evaluated in human melanoma cell lines (SK-MEL-147, CHL-1, WM1366), revealing greater cytotoxic activity on CHL-1 line an IC50 14.50 ± 1.09 µM. Subsequent studies showed inhibits proliferation cells induces apoptosis, associated at least part pro-oxidant effect cycle arrest G1/S transition.

Language: Английский

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Overview of Wnt/β-Catenin Pathway and DNA Damage/Repair in Cancer

Biology, Journal Year: 2025, Volume and Issue: 14(2), P. 185 - 185

Published: Feb. 11, 2025

The Wnt/β-catenin pathway takes part in important cellular processes tumor cells, such as gene expression, adhesion, and survival. canonical is activated several tumors, β-catenin its major effector. union of Wnt to the co-receptor complex causes inhibition GSK3β activity, thus preventing phosphorylation degradation β-catenin, which accumulates cytoplasm, subsequently be transported nucleus associate with transcription factors. relationship between DNA damage/repair mechanisms has been a focus for last few years. Studying network interactions proteins become successful research field. This review provides an overview participation their future implications targets cancer therapy.

Language: Английский

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CellTool: An Open-Source Software Combining Bio-Image Analysis and Mathematical Modeling for the Study of DNA Repair Dynamics

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(23), P. 16784 - 16784

Published: Nov. 26, 2023

Elucidating the dynamics of DNA repair proteins is essential to understanding mechanisms that preserve genomic stability and prevent carcinogenesis. However, measurement modeling protein at lesions via currently available image analysis tools cumbersome. Therefore, we developed CellTool-a stand-alone open-source software with a graphical user interface for time-lapse microscopy images. It combines data management, processing, mathematical modeling, presentation in single package. Multiple filters, segmentation, particle tracking algorithms, combined direct visualization obtained results, make CellTool an ideal application comprehensive dynamics. This enables fitting kinetic predefined or custom models. Importantly, provides platform easy implementation packages written variety programing languages. Using CellTool, demonstrate ALKB homolog 2 (ALKBH2) demethylase excluded from damage sites despite recruitment its putative interaction partner proliferating cell nuclear antigen (PCNA). Further, facilitates straightforward fluorescence recovery after photobleaching (FRAP) BRCA1 associated RING domain 1 (BARD1) exchange complex lesions. In summary, presented herein time-efficient wide range experiments through user-friendly interface.

Language: Английский

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Cellular Responses to Widespread DNA Replication Stress

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(23), P. 16903 - 16903

Published: Nov. 29, 2023

Replicative DNA polymerases are blocked by nearly all types of damage. The resulting replication stress threatens genome stability. is also caused depletion nucleotide pools, polymerase inhibitors, and sequences or structures that difficult to replicate. Replication triggers complex cellular responses include cell cycle arrest, fork collapse one-ended double-strand breaks, induction repair, programmed death after excessive specific (e.g., G-rich form G-quadruplexes) localized but occurs during the S phase every division. This review focuses on widespread such as random damage, inhibition/nucleotide pool depletion, R-loops. Another global seen in cancer cells termed oncogenic stress, reflecting dysregulated origin firing and/or progression. often cells, this too contributes ongoing instability can drive Nucleases play critical roles responses, including MUS81, EEPD1, Metnase, CtIP, MRE11, EXO1, DNA2-BLM, SLX1-SLX4, XPF-ERCC1-SLX4, Artemis, XPG, FEN1, TATDN2. Several these nucleases cleave branched at stressed forks promote repair restart forks. We recently defined for EEPD1 restarting oxidative TATDN2 mitigating R-loop accumulation BRCA1-defective cells. discuss how insights into biological genome-wide inform novel treatment strategies exploit synthetic lethal relationships among response factors.

Language: Английский

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CCAR1 promotes DNA repair via alternative splicing

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(14), P. 2634 - 2647.e9

Published: July 1, 2024

Language: Английский

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High Glucose Increases DNA Damage and Elevates the Expression of Multiple DDR Genes

Genes, Journal Year: 2023, Volume and Issue: 14(1), P. 144 - 144

Published: Jan. 5, 2023

The DNA Damage Response (DDR) pathways sense damage and coordinate robust repair bypass mechanisms. A series of proteins are recruited depending on the type breaks lesions to ensure overall survival. An increase in glucose levels was shown induce genome instability, yet links between DDR still not well investigated. In this study, we aimed identify dysregulation transcriptome normal cancerous breast cell lines upon changing levels. We first performed bioinformatics analysis using a microarray dataset containing triple-negative cancer (TNBC) MDA-MB-231 human mammary epithelium MCF10A grown high (HG) or presence glycolysis inhibitor 2-deoxyglucose (2DG). Interestingly, multiple genes were significantly upregulated both HG. wet lab, remarkably found that HG results severe TNBC cells as observed comet assay. addition, several confirmed be qPCR same line. Our propose strong need for oppose induced cells.

Language: Английский

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