scholarly journals Evaluation of Biological Effect in Breast Cell Irradiated with Dose 2 Gy in Radiotherapy

2021 ◽  
Author(s):  
Leslie Pereira ◽  
Antonio Gilcler F. Lima ◽  
Marcella T. Ferreira ◽  
Camila Salata ◽  
Samara C Ferreira-Machado ◽  
...  
Keyword(s):  
Single Dose ◽  
Tumor Cell ◽  
Cell Lines ◽  
Distant Recurrence ◽  
Definitive Treatment ◽  
Dna Breaks ◽  
Cellular Microenvironment ◽  
Ir Studies ◽  
Double Strand Dna Breaks ◽  
Unsuccessful Treatment

Abstract Introduction: Breast cancer (BC) is the most common female malignancy worldwide. For the definitive treatment of MC, radiotherapy can be used, as an important component, and uses ionizing radiation (IR). Studies reveal the potential capacity of IR to promote metastasis. The clinical response of BC to radiotherapy is related to radiosensitivity and resistance of irradiated cells, which is associated with clonogenic activity and sensitivity to radiation. Unsuccessful treatment increases the risk of local and distant recurrence.Methodology: Three breast cell lines (MCF-10A, MCF-7, and MDA-MB-231) were irradiated with 2 Gy and after 72 hours following markers were evaluated: E-cadherin, fibronectin, vimentin, and Snail. The processes of invasion, degradation of MMP2 and MMP9, and transendothelial migration were then assessed. Double-strand DNA breaks (DSBs), apoptosis, and colony formation were quantified. Result: The detection of γH2AX histone of irradiated cells showed that MCF-10A non-tumor cell is more radiosensitive while the MDA-MB-231 tumor cell is more radioresistant. The dose 2 Gy altered the formation of colonies to any of the cell lines. Tumorigenic cells exhibited a markedly increase in apoptosis, 24 h after irradiation while MCF-10A cells only after 72 h. A single dose of 2 Gy does not induce changes in the cellular microenvironment that lead to changes in the mesenchymal epithelium in breast BC.Conclusion: A dose of 2 Gy induces apoptosis and consequently an alteration in cell survival. However, a single dose of 2 Gy does not induce changes in the cellular microenvironment that lead to changes in the mesenchymal epithelium.

scholarly journals WRN Helicase is a Synthetic Lethal Target in Microsatellite Unstable Cancers

2018 ◽  
Author(s):  
Edmond Chan ◽  
Tsukasa Shibue ◽  
James McFarland ◽  
Benjamin Gaeta ◽  
Justine McPartlan ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cell Lines ◽  
Large Scale ◽  
Synthetic Lethality ◽  
Cancer Therapeutics ◽  
Dna Helicase ◽  
Dna Breaks ◽  
Synthetic Lethal ◽  
Dna Mismatch ◽  
Double Strand Dna Breaks

Synthetic lethality, an interaction whereby the co-occurrence of two or more genetic events lead to cell death but one event alone does not, can be exploited to develop novel cancer therapeutics. DNA repair processes represent attractive synthetic lethal targets since many cancers exhibit an impaired DNA repair pathway, which can lead these cells to become dependent on specific repair proteins. The success of poly (ADP-ribose) polymerase 1 (PARP-1) inhibitors in homologous recombination-deficient cancers highlights the potential of this approach in clinical oncology. Hypothesizing that other DNA repair defects would give rise to alternative synthetic lethal relationships, we asked if there are specific dependencies in cancers with microsatellite instability (MSI), which results from impaired DNA mismatch repair (MMR). Here we analyzed data from large-scale CRISPR/Cas9 knockout and RNA interference (RNAi) silencing screens and found that the RecQ DNA helicase was selectively essential in MSI cell lines, yet dispensable in microsatellite stable (MSS) cell lines. WRN depletion induced double-strand DNA breaks and promoted apoptosis and cell cycle arrest selectively in MSI models. MSI cancer models specifically required the helicase activity, but not the exonuclease activity of WRN. These findings expose WRN as a synthetic lethal vulnerability and promising drug target in MSI cancers.

scholarly journals DDRE-24. TARGETING PURINE METABOLISM TO OVERCOME GLIOBLASTOMA THERAPY RESISTANCE

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i11-i11
Author(s):  
Weihua Zhou ◽  
Yangyang Yao ◽  
Andrew Scott ◽  
Kari Wilder-Romans ◽  
Joseph Dresser ◽  
...  
Keyword(s):  
Cell Lines ◽  
De Novo ◽  
Therapy Resistance ◽  
Dna Breaks ◽  
Purine Synthesis ◽  
Double Strand Dna Breaks ◽  
Ability To Act ◽  
Orally Bioavailable

Abstract Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming radiation (RT) resistance. To discover genotype-independent mediators of RT resistance, we correlated RT resistance with the concentration of approximately 700 metabolites across 23 GBM cell lines. Purine metabolites, especially those containing the base guanine, were most correlated with RT resistance. Similarly, increased abundance of tumor purines was associated with decreased survival in GBM patients treated with RT. This relationship is causal. Purine supplementation protected RT-sensitive GBMs from RT and promoted the repair of RT-induced double strand DNA breaks (DSBs). In vitro and in vivo stable isotope tracing confirmed that GBM cell lines and orthotopic patient-derived xenografts primarily generated purines through the de novo synthetic pathway. RT treatment further increased de novo purine synthesis in GBM through signaling via the DNA damage response. Inhibition of de novo GTP synthesis with mycophenolic acid (MPA) sensitized multiple GBM cell lines and neurospheres to RT by slowing the repair of RT-induced DSBs. MPA-induced radiosensitization was GTP-dependent as it was rescued by nucleoside supplementation. Modulating pyrimidine metabolism affected neither RT resistance nor DSB repair, suggesting these GTP-specific effects are due to active signaling rather than its ability to act as a physical substrate for DNA repair and candidate signaling molecules have been identified. These results were recapitulated in vivo with mycophenolate mofetil (MMF), the orally bioavailable FDA-approved prodrug of MPA. MMF potentiated RT efficacy, reduced tumor guanylates and slowed the repair of RT-induced DSBs across multiple models. Because de novo purine synthesis is activated by many of the oncogenic alterations that drive GBM, its inhibition is a promising genotype-independent strategy to overcome GBM RT resistance. We have now begun a clinical trial to determine whether combining MMF and RT is safe and potentially efficacious in patients with GBM.

Interaction of Human Tumor Cells with Human Platelets and the Coagulation System

1983 ◽  
Vol 50 (03) ◽  
pp. 726-730 ◽  
Author(s):  
Hamid Al-Mondhiry ◽  
Virginia McGarvey ◽  
Kim Leitzel
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Cell Lines ◽  
Human Tumor ◽  
Human Platelets ◽  
Factor Vii ◽  
Coagulation System ◽  
Breast Adenocarcinoma ◽  
Activate Factor ◽  
Tumor Cell Lines

SummaryThis paper reports studies on the interaction between human platelets, the plasma coagulation system, and two human tumor cell lines grown in tissue culture: Melanoma and breast adenocarcinoma. The interaction was monitored through the use of 125I- labelled fibrinogen, which measures both thrombin activity generated by cell-plasma interaction and fibrin/fibrinogen binding to platelets and tumor cells. Each tumor cell line activates both the platelets and the coagulation system simultaneously resulting in the generation of thrombin or thrombin-like activity. The melanoma cells activate the coagulation system through “the extrinsic pathway” with a tissue factor-like effect on factor VII, but the breast tumor seems to activate factor X directly. Both tumor cell lines activate platelets to “make available” a platelet- derived procoagulant material necessary for the conversion of prothrombin to thrombin. The tumor-derived procoagulant activity and the platelet aggregating potential of cells do not seem to be inter-related, and they are not specific to malignant cells.

Prime-editors (nickases), hRad51–Cas9 nickase fusions and dCas9 have the same problem as conventional CRISPR-Cas9 of plasmid/Cas9 integration after making a double stranded break

2019 ◽  
Author(s):  
Sandeep Chakraborty
Keyword(s):  
Cellular Response ◽  
Sequencing Data ◽  
Dna Breaks ◽  
Precise Integration ◽  
Guide Rna ◽  
Double Strand Dna Breaks ◽  
Human Therapy ◽  
P53 Activation ◽  
Programmable Nucleases

‘Prime-editing’ proposes to replace traditional programmable nucleases (CRISPR-Cas9) using a catalytically impaired Cas9 (dCas9) connected to a engineered reverse transcriptase, and a guide RNA encoding both the target site and the desired change. With just a ‘nick’ on one strand, it is hypothe- sized, the negative, uncontrollable effects arising from double-strand DNA breaks (DSBs) - translocations, complex proteins, integrations and p53 activation - will be eliminated. However, sequencing data pro- vided (Accid:PRJNA565979) reveal plasmid integration, indicating that DSBs occur. Also, looking at only 16 off-targets is inadequate to assert that Prime-editing is more precise. Integration of plasmid occurs in all three versions (PE1/2/3). Interestingly, dCas9 which is known to be toxic in E. coli and yeast, is shown to have residual endonuclease activity. This also affects studies that use dCas9, like base- editors and de/methylations systems. Previous work using hRad51–Cas9 nickases also show significant integration in on-targets, as well as off-target integration [1]. Thus, we show that cellular response to nicking involves DSBs, and subsequent plasmid/Cas9 integration. This is an unacceptable outcome for any in vivo application in human therapy.

Differential Increases in Glutathione S-Transferase Activities in a Range of Multidrug-Resistant Human Tumor Cell Lines

1989 ◽  
Vol 1 (6) ◽  
pp. 359-365 ◽  
Author(s):  
Richard D. H. Whelan ◽  
Louise K. Hosking ◽  
Alan J. Townsend ◽  
Kenneth H. Cowan ◽  
Bridget T. Hill
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Human Tumor ◽  
Multidrug Resistant ◽  
Tumor Cell Lines ◽  
Glutathione S Transferase ◽  
Human Tumor Cell ◽  
Human Tumor Cell Lines

Cytotoxic Activities of Red Algae Collected from Jeju Island Against Four Tumor Cell Lines

2006 ◽  
Vol 11 (3) ◽  
pp. 177-183 ◽  
Author(s):  
Kil-Nam Kim ◽  
Ki-Wan Lee ◽  
Choon-Bok Song ◽  
Chang-Bum Ahn ◽  
You-Jin Jeon
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Red Algae ◽  
Jeju Island ◽  
Cytotoxic Activities ◽  
Tumor Cell Lines

Synthesis and Cytotoxicity of New Mannich Bases of 6-[3-(3,4,5-Trimetoxyphenyl)-2- propenoyl]-2(3H)-Benzoxazolone

2020 ◽  
Vol 17 (4) ◽  
pp. 512-517
Author(s):  
Ognyan Ivanov Petrov ◽  
Yordanka Borisova Ivanova ◽  
Mariana Stefanova Gerova ◽  
Georgi Tsvetanov Momekov
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Biological Activities ◽  
Human Tumor ◽  
Mannich Bases ◽  
In Vitro Cytotoxicity ◽  
Tumor Cell Lines ◽  
Human Tumor Cell ◽  
Human Tumor Cell Lines

Background: Chemotherapy is one of the mainstays of cancer treatment, despite the serious side effects of the clinically available anticancer drugs. In recent years increasing attention has been directed towards novel agents with improved efficacy and selectivity. Compounds with chalcone backbone have been reported to possess various biological activities such as anticancer, antimicrobial, anti-inflammatory, analgesic, antioxidant, etc. It was reported that aminomethylation of hydroxy chalcones to the corresponding Mannich bases increased their cytotoxicity. In this context, our interest has been focused on the design and synthesis of the so-called multi-target molecules, containing two or more pharmacophore fragments. Methods: A series of Mannich bases were synthesized by the reaction between 6-[3-(3,4,5- trimethoxyphenyl)-2-propenoyl]-2(3Н)-benzoxazolone, formaldehyde, and a secondary amine. The structures of the compounds were confirmed by elemental analysis, IR and NMR spectra. The new Mannich bases were evaluated for their in vitro cytotoxicity against a panel of human tumor cell lines, including BV-173, SKW-3, K-562, HL-60, HD-MY-Z and MDA-MB-231. The effects of selected compounds on the cellular levels of glutathione (GSH) were determined. Results: The new compounds 4a-e exhibited concentration-dependent cytotoxic effects at micromolar concentrations in MTT-dye reduction assay against a panel of human tumor cell lines, similar to those of starting chalcone 3. The tested agents led to concentration - dependent depletion of cellular GSH levels, whereby the effects of the chalcone prototype 3 and its Mannich base-derivatives were comparable. Conclusion: The highest chemosensitivity to the tested compounds was observed in BV- 173followed by SKW-3 and HL-60 cell lines.

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