Effect of Pterostilbene, a Natural Derivative of Resveratrol, in the Treatment of Colorectal Cancer through Top1/Tdp1-Mediated DNA Repair Pathway.
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ABSTRACT:
SUBMITTER: Zhang Y
PROVIDER: S-EPMC8391236 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Anticancer drugs, such as camptothecin (CPT), trap topoisomerase I (TOP1) on DNA and form TOP1 cleavage complexes (TOP1cc). Alternative repair pathways have been suggested in the repair of TOP1cc. However, how these pathways work with TDP1, a key repair enzyme that specifically hydrolyze the covalent bond between TOP1 catalytic tyrosine and the 3'-end of DNA and contribute to the repair of TOP1cc is poorly understood. Here, using unbiased whole-genome CRISPR screens and generation of co-deficient cells with TDP1 and other genes, we demonstrate that MUS81 is an important factor that mediates the generation of excess double-strand breaks (DSBs) in TDP1 KO cells. APEX1/2 are synthetic lethal with TDP1. However, deficiency of APEX1/2 does not reduce DSB formation in TDP1 KO cells. Together, our data suggest that TOP1cc can be either resolved directly by TDP1 or be converted into DSBs and repaired further by the Homologous Recombination (HR) pathway.
| S-EPMC9307636 | biostudies-literature
Project description:In this study, amorphous solid dispersions (ASDs) of pterostilbene (PTR) with polyvinylpyrrolidone polymers (PVP K30 and VA64) were prepared through milling, affirming the amorphous dispersion of PTR via X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Subsequent analysis of DSC thermograms, augmented using mathematical equations such as the Gordon-Taylor and Couchman-Karasz equations, facilitated the determination of predicted values for glass transition (Tg), PTR's miscibility with PVP, and the strength of PTR's interaction with the polymers. Fourier-transform infrared (FTIR) analysis validated interactions maintaining PTR's amorphous state and identified involved functional groups, namely, the 4'-OH and/or -CH groups of PTR and the C=O group of PVP. The study culminated in evaluating the impact of amorphization on water solubility, the release profile in pH 6.8, and in vitro permeability (PAMPA-GIT and BBB methods). In addition, it was determined how improving water solubility affects the increase in antioxidant (ABTS, DPPH, CUPRAC, and FRAP assays) and neuroprotective (inhibition of cholinesterases: AChE and BChE) properties. The apparent solubility of the pure PTR was ~4.0 µg·mL-1 and showed no activity in the considered assays. For obtained ASDs (PTR-PVP30/PTR-PVPVA64, respectively) improvements in apparent solubility (410.8 and 383.2 µg·mL-1), release profile, permeability, antioxidant properties (ABTS: IC50 = 52.37/52.99 μg·mL-1, DPPH: IC50 = 163.43/173.96 μg·mL-1, CUPRAC: IC0.5 = 122.27/129.59 μg·mL-1, FRAP: IC0.5 = 95.69/98.57 μg·mL-1), and neuroprotective effects (AChE: 39.1%/36.2%, BChE: 76.9%/73.2%) were confirmed.
| S-EPMC10932125 | biostudies-literature
Project description:Topoisomerase 1 (Top1) controls DNA topology, relieves DNA supercoiling during replication and transcription, and is critical for mitotic progression to the G1 phase. Tyrosyl-DNA phosphodiesterase 1 (TDP1) mediates the removal of trapped Top1-DNA covalent complexes (Top1cc). Here, we identify CDK1-dependent phosphorylation of TDP1 at residue S61 during mitosis. A TDP1 variant defective for S61 phosphorylation (TDP1-S61A) is trapped on the mitotic chromosomes, triggering DNA damage and mitotic defects. Moreover, we show that Top1cc repair in mitosis occurs via a MUS81-dependent DNA repair mechanism. Replication stress induced by camptothecin or aphidicolin leads to TDP1-S61A enrichment at common fragile sites, which over-stimulates MUS81-dependent chromatid breaks, anaphase bridges, and micronuclei, ultimately culminating in the formation of 53BP1 nuclear bodies during G1 phase. Our findings provide new insights into the cell cycle-dependent regulation of TDP1 dynamics for the repair of trapped Top1-DNA covalent complexes during mitosis that prevents genomic instability following replication stress.
| S-SCDT-10_1038-S44318-024-00169-3 | biostudies-other
Project description:Pterostilbene is a methoxylated derivative of resveratrol originated from natural sources. We investigated the antibacterial activity of pterostilbene against drug-resistant Staphylococcus aureus and the feasibility of using it to treat cutaneous bacteria. The antimicrobial effect was evaluated using an in vitro culture model and an in vivo mouse model of cutaneous infection. The minimum inhibitory concentration (MIC) assay demonstrated a superior biocidal activity of pterostilbene compared to resveratrol (8~16-fold) against methicillin-resistant S. aureus (MRSA) and clinically isolated vancomycin-intermediate S. aureus (VISA). Pterostilbene was found to reduce MRSA biofilm thickness from 18 to 10 ?m as detected by confocal microscopy. Pterostilbene showed minimal toxicity to THP-1 cells and was readily engulfed by the macrophages, facilitating the eradication of intracellular MRSA. Pterostilbene exhibited increased skin absorption over resveratrol by 6-fold. Topical pterostilbene application improved the abscess formation produced by MRSA by reducing the bacterial burden and ameliorating the skin architecture. The potent anti-MRSA capability of pterostilbene was related to bacterial membrane leakage, chaperone protein downregulation, and ribosomal protein upregulation. This mechanism of action was different from that of resveratrol according to proteomic analysis and molecular docking. Pterostilbene has the potential to serve as a novel class of topically applied agents for treating MRSA infection in the skin while demonstrating less toxicity to mammalian cells.
| S-EPMC5468402 | biostudies-literature
Project description:Background: Pterostilbene, a naturally occurring phenolic compound produced by agronomically important plant genera such as Vitis and Vacciunium, is a phytoalexin exhibiting potent antifungal activity. Additionally, recent studies have demonstrated several important pharmacological properties associated with pterostilbene. Despite this, a systematic study of the effects of pterostilbene on eukaryotic cells at the molecular level has not been previously reported. Thus, the aim of the present study was to identify the cellular pathways affected by pterostilbene by performing transcript profiling studies, employing the model yeast Saccharomyces cerevisiae. Methods: S. cerevisiae strain S288C was exposed to pterostilbene at the IC50 concentration (70 uM) for one generation (3 h). Transcript profiling experiments were performed on three biological replicate samples using the Affymetrix GeneChip Yeast Genome S98 Array. The data were analyzed using the statistical methods available in the GeneSifter microarray data analysis system. To validate the results, eleven differentially expressed genes were further examined by quantitative real-time RT-PCR, and S. cerevisiae mutant strains with deletions in these genes were analyzed for altered sensitivity to pterostilbene. Results: Transcript profiling studies revealed that pterostilbene exposure significantly down-regulated the expression of genes involved in methionine metabolism, while the expression of genes involved in mitochondrial functions, drug detoxification, and transcription factor activity were significantly up-regulated. Additional analyses revealed that a large number of genes involved in lipid metabolism were also affected by pterostilbene treatment. Conclusions: Using transcript profiling, we have identified the cellular pathways targeted by pterostilbene, an analog of resveratrol. The observed response in lipid metabolism genes is consistent with its known hypolipidemic properties, and the induction of mitochondrial genes is consistent with its demonstrated role in apoptosis in human cancer cell lines. Furthermore, our data show that pterostilbene has a significant effect on methionine metabolism, a previously unreported effect for this compound. Keywords: Transcript profiling, S. cerevisiae, pterostilbene
2008-03-05 | GSE10554 | GEO
Project description:Pterostilbene, a naturally occurring phenolic compound produced by agronomically important plant genera such as Vitis and Vacciunium, is a phytoalexin exhibiting potent antifungal activity. Additionally, recent studies have demonstrated several important pharmacological properties associated with pterostilbene. Despite this, a systematic study of the effects of pterostilbene on eukaryotic cells at the molecular level has not been previously reported. Thus, the aim of the present study was to identify the cellular pathways affected by pterostilbene by performing transcript profiling studies, employing the model yeast Saccharomyces cerevisiae.S. cerevisiae strain S288C was exposed to pterostilbene at the IC50 concentration (70 muM) for one generation (3 h). Transcript profiling experiments were performed on three biological replicate samples using the Affymetrix GeneChip Yeast Genome S98 Array. The data were analyzed using the statistical methods available in the GeneSifter microarray data analysis system. To validate the results, eleven differentially expressed genes were further examined by quantitative real-time RT-PCR, and S. cerevisiae mutant strains with deletions in these genes were analyzed for altered sensitivity to pterostilbene.Transcript profiling studies revealed that pterostilbene exposure significantly down-regulated the expression of genes involved in methionine metabolism, while the expression of genes involved in mitochondrial functions, drug detoxification, and transcription factor activity were significantly up-regulated. Additional analyses revealed that a large number of genes involved in lipid metabolism were also affected by pterostilbene treatment.Using transcript profiling, we have identified the cellular pathways targeted by pterostilbene, an analog of resveratrol. The observed response in lipid metabolism genes is consistent with its known hypolipidemic properties, and the induction of mitochondrial genes is consistent with its demonstrated role in apoptosis in human cancer cell lines. Furthermore, our data show that pterostilbene has a significant effect on methionine metabolism, a previously unreported effect for this compound.
| S-EPMC2330146 | biostudies-literature
Project description:Background: Pterostilbene, a naturally occurring phenolic compound produced by agronomically important plant genera such as Vitis and Vacciunium, is a phytoalexin exhibiting potent antifungal activity. Additionally, recent studies have demonstrated several important pharmacological properties associated with pterostilbene. Despite this, a systematic study of the effects of pterostilbene on eukaryotic cells at the molecular level has not been previously reported. Thus, the aim of the present study was to identify the cellular pathways affected by pterostilbene by performing transcript profiling studies, employing the model yeast Saccharomyces cerevisiae. Methods: S. cerevisiae strain S288C was exposed to pterostilbene at the IC50 concentration (70 uM) for one generation (3 h). Transcript profiling experiments were performed on three biological replicate samples using the Affymetrix GeneChip Yeast Genome S98 Array. The data were analyzed using the statistical methods available in the GeneSifter microarray data analysis system. To validate the results, eleven differentially expressed genes were further examined by quantitative real-time RT-PCR, and S. cerevisiae mutant strains with deletions in these genes were analyzed for altered sensitivity to pterostilbene. Results: Transcript profiling studies revealed that pterostilbene exposure significantly down-regulated the expression of genes involved in methionine metabolism, while the expression of genes involved in mitochondrial functions, drug detoxification, and transcription factor activity were significantly up-regulated. Additional analyses revealed that a large number of genes involved in lipid metabolism were also affected by pterostilbene treatment. Conclusions: Using transcript profiling, we have identified the cellular pathways targeted by pterostilbene, an analog of resveratrol. The observed response in lipid metabolism genes is consistent with its known hypolipidemic properties, and the induction of mitochondrial genes is consistent with its demonstrated role in apoptosis in human cancer cell lines. Furthermore, our data show that pterostilbene has a significant effect on methionine metabolism, a previously unreported effect for this compound. Experiment Overall Design: S. cerevisiae S288C cells at OD 0.2 were treated with either pterostilbene (Ptero) at IC50 concentration (70 uM), or solvent (0.25% DMSO), allowed to grow to OD 0.5, then harvested and frozen. Three biological replicate samples were analyzed for each treatment.
2008-04-06 | E-GEOD-10554 | biostudies-arrayexpress
Project description:When a replication fork collides with a DNA topoisomerase I (Top1) cleavage complex, the covalently bound enzyme must be removed from the DNA 3' end before recombination-dependent replication restart. Here we report that the tyrosyl-DNA phosphodiesterase Tdp1 and the structure-specific endonuclease Rad1-Rad10 function as primary alternative pathways of Top1 repair in Saccharomyces cerevisiae. Thus, tdp1 rad1 cells (including the catalytic point mutant rad1-D869A) not only are highly sensitive to the Top1 poison camptothecin but also exhibit a TOP1-dependent growth delay. Extensive genetic analysis revealed that both Tdp1 and Rad1-Rad10 repair proceed through recombination that equally depends on RAD52, RAD51, and RAD50. The Rad1-Rad10 pathway further particularly depends on RAD59 and SRS2 but is independent of other nucleotide excision repair genes. Although this pattern is consistent with Rad1-Rad10 removing Top1 in a manner similar to its removal of nonhomologous tails during gene conversion, these differ in that Top1 removal does not require Msh2-Msh3. Finally, we show that yeast lacking the Rad1-Rad10-related proteins Mus81-Mms4 display a unique pattern of camptothecin sensitivity and suggest a concerted model for the action of these endonucleases.
| S-EPMC129737 | biostudies-literature
Project description:The aim of this study was to elucidate the carryover effect of olaparib to subsequent chemotherapy and its underlying mechanisms. We generated olaparib-resistant SNU-484, SNU-601, SNU-668, and KATO-III gastric cancer cell lines and confirmed their resistance by cell viability and colony forming assays. Notably, olaparib-resistant cell lines displayed cross-resistance to cisplatin except for KATO-III. Inversely, olaparib-resistant SNU-484, SNU-668, and KATO-III were more sensitive to irinotecan than their parental cells. However, sensitivity to paclitaxel remained unaltered. There were compensatory changes in the ATM/ATR axis and p-Chk1/2 protein expression. ERCC1 was also induced in olaparib-resistant SNU-484, SNU-601, and SNU-668, which showed cross-resistance to cisplatin. Olaparib-resistant cells showed tyrosyl-DNA phosphodiesterase 1 (TDP1) downregulation with higher topoisomerase 1 (TOP1) activity, which is a target of irinotecan. These changes of TOP1 and TDP1 in olaparib-resistant cells was confirmed as the underlying mechanism for increased irinotecan sensitivity through manipulated gene expression of TOP1 and TDP1 by specific plasmid transfection and siRNA. The patient-derived xenograft model established from the patient who acquired resistance to olaparib with BRCA2 mutation showed increased sensitivity in irinotecan. In conclusion, the carryover effects of olaparib to improve antitumor effect of subsequent irinotecan were demonstrated. These effects should be considered when determining the subsequent therapy with olaparib.
| S-EPMC7072281 | biostudies-literature
Project description:BackgroundIntestinal disorder is an important factor contributing to growth lag and high rates of morbidity and mortality of piglets with intrauterine growth retardation (IUGR). Resveratrol (RSV) and its derivative pterostilbene (PT) are natural stilbenes possessing various bioactivities, such as antioxidative and anti-inflammatory effects. This study compared the protective potential of RSV and PT on the intestinal redox status and gut microbiota in weanling piglets with IUGR.MethodsEighteen male piglets of normal body weight (NBW) and 54 same-sex IUGR piglets were chosen according to their birth and weaning weights. The NBW piglets accepted a basal diet, while the IUGR piglets were allotted to one of three groups according to their body weight at weaning and received a basal diet, an RSV-supplemented diet (300 mg/kg), or a PT-supplemented diet (300 mg/kg), respectively.ResultsCompared with IUGR piglets, both RSV and PT improved the IUGR-associated decrease in jejunal villus height and increases in plasma diamine oxidase activity and D-lactate level and jejunal apoptosis of piglets (P < 0.05). Administering RSV and PT also enhanced jejunal superoxide dismutase activity and the mRNA and protein expression of superoxide dismutase 2 of IUGR piglets by promoting nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation (P < 0.05). Comparatively, PT was more effective than RSV in elevating the villus height/crypt depth ratio and occludin mRNA and protein levels in the jejunum of IUGR piglets (P < 0.05). PT was also superior to RSV in increasing Nrf2 nuclear translocation and inhibiting malondialdehyde accumulation in the jejunum of IUGR piglets (P < 0.05). Additionally, RSV modulated the composition of cecal microbiota of IUGR piglets, as evidenced by increasing the prevalence of the phylum Bacteroidetes and the genera Prevotella, Faecalibacterium, and Parabacteroides and inhibiting the growth of the phylum Proteobacteria and its genera Escherichia and Actinobacillus (P < 0.05). Moreover, RSV significantly increased the butyrate concentration in the cecum of IUGR piglets (P < 0.05).ConclusionPT is more potent than RSV to prevent intestinal oxidative stress, while RSV has a stronger capacity to regulate gut microbiota compared to PT.
| S-EPMC8191009 | biostudies-literature