scholarly journals Synthesis Novel Fluorinated Cyclic Nanomeric Aza Crown Macrocyclic System Containing 1,2,4-triazine moiety and Ru-complex as Cyclin-dependent kinase 2 (CDK2) inhibitors of tumor cells (Protection of DNA Damage)-Part II

2020 ◽  
Vol 36 (6) ◽  
pp. 1113-1118
Author(s):  
Wafa A. Bawazir ◽  
Reda M. Abdel -Rahman
Keyword(s):  
Dna Damage ◽  
Tumor Cells ◽  
Elemental Analysis ◽  
Diethyl Oxalate ◽  
Cyclin Dependent Kinase ◽  
Spectral Measurements ◽  
Ru Complex ◽  
Ic50 Values ◽  
Potential Activity ◽  
Macrocyclic System

Novel fluorinated 1,5-disubstituted-1,3,5-triazepine-6,7-dione (4) has been obtained from the interaction between 5,6-bis(4-fluorophenyl)-1,2,4-triazine-3-thiol (1) with 2,6-diaminopyridine 2 followed by ring closer reaction with diethyl oxalate. Also, Ru-complex 7 obtained by refluxing of compound 1 with 6-(4-fluorophenyl)-1,2,4-triazine-3,5-diamine (5) to produce compound 6, the later was reacted with RuCl3.xH2O to produce the target 7. Structures of the products deduced from their elemental analysis and spectral measurements. Compounds 3, 4, 6, and 7 were evaluated as CDK2 inhibitors of tumor cells; these compounds exhibited a potential activity against CDK2, where the IC50 values were 4.5, 6.8, 4.0, and 5.0 μM respectively in comparison with Olomoucine standard (IC50=5.0 μM).

scholarly journals Cell cycle inertia underlies a bifurcation in cell fates after DNA damage

2021 ◽  
Vol 7 (3) ◽  
pp. eabe3882
Author(s):  
Jenny F. Nathans ◽  
James A. Cornwell ◽  
Marwa M. Afifi ◽  
Debasish Paul ◽  
Steven D. Cappell
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cell Tracking ◽  
Time Lapse ◽  
S Phase ◽  
Cdk Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Cell Fates ◽  
Damage Response ◽  
Time Lapse Imaging

The G1-S checkpoint is thought to prevent cells with damaged DNA from entering S phase and replicating their DNA and efficiently arrests cells at the G1-S transition. Here, using time-lapse imaging and single-cell tracking, we instead find that DNA damage leads to highly variable and divergent fate outcomes. Contrary to the textbook model that cells arrest at the G1-S transition, cells triggering the DNA damage checkpoint in G1 phase route back to quiescence, and this cellular rerouting can be initiated at any point in G1 phase. Furthermore, we find that most of the cells receiving damage in G1 phase actually fail to arrest and proceed through the G1-S transition due to persistent cyclin-dependent kinase (CDK) activity in the interval between DNA damage and induction of the CDK inhibitor p21. These observations necessitate a revised model of DNA damage response in G1 phase and indicate that cells have a G1 checkpoint.

scholarly journals Apoptosis mediated chemosensitization of tumor cells to 5-fluorouracil on supplementation of fish oil in experimental colon carcinoma

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769501 ◽  
Author(s):  
Isha Rani ◽  
Bhoomika Sharma ◽  
Sandeep Kumar ◽  
Satinder Kaur ◽  
Navneet Agnihotri
Keyword(s):  
Fatty Acids ◽  
Dna Damage ◽  
Polyunsaturated Fatty Acids ◽  
Fish Oil ◽  
Tumor Cells ◽  
Apoptotic Index ◽  
Apoptotic Pathway ◽  
Apoptotic Effect ◽  
Underlying Mechanisms ◽  
Apoptotic Pathways

5-Fluorouracil has been considered as a cornerstone therapy for colorectal cancer; however, it suffers from low therapeutic response rate and severe side effects. Therefore, there is an urgent need to increase the clinical efficacy of 5-fluorouracil. Recently, fish oil rich in n-3 polyunsaturated fatty acids has been reported to chemosensitize tumor cells to anti-cancer drugs. This study is designed to understand the underlying mechanisms of synergistic effect of fish oil and 5-fluorouracil by evaluation of tumor cell–associated markers such as apoptosis and DNA damage. The colon cancer was developed by administration of N,N-dimethylhydrazine dihydrochloride and dextran sulfate sodium salt. Further these animals were treated with 5-fluorouracil, fish oil, or a combination of both. In carcinogen-treated animals, a decrease in DNA damage and apoptotic index was observed. There was also a decrease in the expression of Fas, FasL, caspase 8, and Bax, and an increase in Bcl-2. In contrast, administration of 5-fluorouracil and fish oil as an adjuvant increased both DNA damage and apoptotic index by activation of both extrinsic and intrinsic apoptotic pathways as compared to the other groups. The increased pro-apoptotic effect by synergism of 5-fluorouracil and fish oil may be attributed to the incorporation of n-3 polyunsaturated fatty acids in membrane, which alters membrane fluidity in cancer cells. In conclusion, this study highlights that the induction of apoptotic pathway by fish oil may increase the susceptibility of tumors to chemotherapeutic regimens.

scholarly journals Overall Cdk activity modulates the DNA damage response in mammalian cells

2009 ◽  
Vol 187 (6) ◽  
pp. 773-780 ◽  
Author(s):  
Antonio Cerqueira ◽  
David Santamaría ◽  
Bárbara Martínez-Pastor ◽  
Miriam Cuadrado ◽  
Oscar Fernández-Capetillo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Cyclin Dependent Kinase ◽  
Genome Maintenance ◽  
Cycle Progression ◽  
Damage Response ◽  
Dna Break ◽  
Specific Contribution

In response to DNA damage, cells activate a phosphorylation-based signaling cascade known as the DNA damage response (DDR). One of the main outcomes of DDR activation is inhibition of cyclin-dependent kinase (Cdk) activity to restrain cell cycle progression until lesions are healed. Recent studies have revealed a reverse connection by which Cdk activity modulates processing of DNA break ends and DDR activation. However, the specific contribution of individual Cdks to this process remains poorly understood. To address this issue, we have examined the DDR in murine cells carrying a defined set of Cdks. Our results reveal that genome maintenance programs of postreplicative cells, including DDR, are regulated by the overall level of Cdk activity and not by specific Cdks.

scholarly journals The synthesis and characterization of some new diazoamino derivatives

2010 ◽  
Vol 16 (1) ◽  
pp. 89-95
Author(s):  
Mihaela Mocanu
Keyword(s):  
1H Nmr ◽  
Bioactive Compounds ◽  
Elemental Analysis ◽  
Analysis Data ◽  
Biological Properties ◽  
Synthesis And Characterization ◽  
Elemental Analysis Data ◽  
Spectral Measurements ◽  
Inflammatory Processes

The sulfonamidic moiety is much encountered in structures of bioactive compounds. In the present paper the studies on the sulfonamidated aryloxyalkylcarboxylic acids are extended by their attaching on certain substrata able to confer some special biological properties to the final products, such as anti-tumor and antioxidant actions useful in treating inflammatory processes, ulcer, convulsions and diabetes, as well as a herbicidal action. The stepwise syntheses of the sulfonamidated aryloxyalkylcarboxylic acid derivatives and their characterization by elemental analysis data and IR, 1H-NMR and UV-Vis spectral measurements are described. The newly obtained compounds could show potential pharmaceutical and herbicide properties.

scholarly journals Bioflavonoid-Induced Apoptosis and DNA Damage in Amastigotes and Promastigotes of Leishmania donovani: Deciphering the Mode of Action

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5843
Author(s):  
Shaila Mehwish ◽  
Sanjay Varikuti ◽  
Mubarak Ali Khan ◽  
Tariq Khan ◽  
Imdad Ullah Khan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Dna Damage ◽  
Leishmania Donovani ◽  
Genetic Material ◽  
Mechanisms Of Action ◽  
Pcr Analysis ◽  
Nitric Oxide Production ◽  
Oxide Production ◽  
Ic50 Values

Natural products from plants contain many interesting biomolecules. Among them, quercetin (Q), gallic acid (GA), and rutin (R) all have well-reported antileishmanial activity; however, their exact mechanisms of action are still not known. The current study is a step forward towards unveil the possible modes of action of these compounds against Leishmania donovani (the causative agent of visceral leishmaniasis). The selected compounds were checked for their mechanisms of action against L. donovani using different biological assays including apoptosis and necrosis evaluation, effects on genetic material (DNA), quantitative testing of nitric oxide production, ultrastructural modification via transmission electron microscopy, and real-time PCR analysis. The results confirmed that these compounds are active against L. donovani, with IC50 values of 84.65 µg/mL, 86 µg/mL, and 98 µg/mL for Q, GA, and R, respectively. These compounds increased nitric oxide production and caused apoptosis and DNA damage, which led to changes in the treated cells’ ultrastructural behavior and finally to the death of L. donovani. These compounds also suppressed essential enzymes like trypanothione reductase and trypanothione synthetase, which are critical for leishmanial survival. The selected compounds have high antileishmanial potentials, and thus in-vivo testing and further screening are highly recommended.

scholarly journals Induction of Oxidative DNA Damage in Bovine Herpesvirus 1 Infected Bovine Kidney Cells (MDBK Cells) and Human Tumor Cells (A549 Cells and U2OS Cells)

Viruses ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 393 ◽  
Author(s):  
Liqian Zhu ◽  
Xiaotian Fu ◽  
Chen Yuan ◽  
Xinyi Jiang ◽  
Gaiping Zhang
Keyword(s):  
Dna Damage ◽  
Virus Infection ◽  
Tumor Cells ◽  
Oxidative Dna Damage ◽  
A549 Cells ◽  
Human Tumor ◽  
Human Tumor Cells ◽  
Bovine Herpesvirus 1 ◽  
Mdbk Cells ◽  
Herpesvirus 1

Bovine herpesvirus 1 (BoHV-1) is an important pathogen of cattle that causes lesions in mucosal surfaces, genital tracts and nervous systems. As a novel oncolytic virus, BoHV-1 infects and kills numerous human tumor cells. However, the mechanisms underlying the virus-induced cell damages are not fully understood. In this study, we demonstrated that virus infection of MDBK cells induced high levels of DNA damage, because the percentage of comet tail DNA (tailDNA%) determined by comet assay, a direct indicator of DNA damage, and the levels of 8-hydroxyguanine (8-oxoG) production, an oxidative DNA damage marker, consistently increased following the virus infection. The expression of 8-oxoguanine DNA glycosylase (OGG-1), an enzyme responsible for the excision of 8-oxoG, was significantly decreased due to the virus infection, which corroborated with the finding that BoHV-1 infection stimulated 8-oxoG production. Furthermore, the virus replication in human tumor cells such as in A549 cells and U2OS cells also induced DNA damage. Chemical inhibition of reactive oxidative species (ROS) production by either ROS scavenger N-Acetyl-l-cysteine or NOX inhibitor diphenylene iodonium (DPI) significantly decreased the levels of tailDNA%, suggesting the involvement of ROS in the virus induced DNA lesions. Collectively, these results indicated that BoHV-1 infection of these cells elicits oxidative DNA damages, providing a perspective in understanding the mechanisms by which the virus induces cell death in both native host cells and human tumor cells.

scholarly journals A comprehensive model for the proliferation–quiescence decision in response to endogenous DNA damage in human cells

2018 ◽  
Vol 115 (10) ◽  
pp. 2532-2537 ◽  
Author(s):  
Frank S. Heldt ◽  
Alexis R. Barr ◽  
Sam Cooper ◽  
Chris Bakal ◽  
Béla Novák
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Kinase Inhibitor ◽  
Human Cells ◽  
Cyclin Dependent Kinase ◽  
Restriction Point ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Serum Stimulation ◽  
G1 Cells ◽  
External Stimuli

Human cells that suffer mild DNA damage can enter a reversible state of growth arrest known as quiescence. This decision to temporarily exit the cell cycle is essential to prevent the propagation of mutations, and most cancer cells harbor defects in the underlying control system. Here we present a mechanistic mathematical model to study the proliferation–quiescence decision in nontransformed human cells. We show that two bistable switches, the restriction point (RP) and the G1/S transition, mediate this decision by integrating DNA damage and mitogen signals. In particular, our data suggest that the cyclin-dependent kinase inhibitor p21 (Cip1/Waf1), which is expressed in response to DNA damage, promotes quiescence by blocking positive feedback loops that facilitate G1 progression downstream of serum stimulation. Intriguingly, cells exploit bistability in the RP to convert graded p21 and mitogen signals into an all-or-nothing cell-cycle response. The same mechanism creates a window of opportunity where G1 cells that have passed the RP can revert to quiescence if exposed to DNA damage. We present experimental evidence that cells gradually lose this ability to revert to quiescence as they progress through G1 and that the onset of rapid p21 degradation at the G1/S transition prevents this response altogether, insulating S phase from mild, endogenous DNA damage. Thus, two bistable switches conspire in the early cell cycle to provide both sensitivity and robustness to external stimuli.

scholarly journals Zinc(II) Terpyridine Complexes: Substituent Effect on Photoluminescence, Antiproliferative Activity, and DNA Interaction

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4519 ◽  
Author(s):  
Jiahe Li ◽  
Rongping Liu ◽  
Jinzhang Jiang ◽  
Xing Liang ◽  
Ling Huang ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Antiproliferative Activity ◽  
Conformational Transition ◽  
Dna Interaction ◽  
Docking Studies ◽  
In Vitro Cytotoxicity ◽  
Human Carcinoma ◽  
Ic50 Values ◽  
The Difference

A series of ZnCl2 complexes (compounds 1–10) with 4′-(substituted-phenyl)-2,2′:6′,2′′-terpyridine that bears hydrogen (L1), p-methyl (L2), p-methoxy (L3), p-phenyl (L4), p-tolyl (L5), p-hydroxyl (L6), m-hydroxyl (L7), o-hydroxyl (L8), p-carboxyl (L9), or p-methylsulfonyl (L10) were prepared and then characterized by 1H NMR, electrospray mass-spectra (ESI-MS), IR, elemental analysis, and single crystal X-ray diffraction. In vitro cytotoxicity assay was used to monitor the antiproliferative activities against tumor cells. Absorption spectroscopy, fluorescence titration, circular dichroism spectroscopy, and molecular modeling studied the DNA interactions. All of the compounds display interesting photoluminescent properties and different maximal emission peaks due to the difference of the substituent groups. The cell viability studies indicate that the compounds have excellent antiproliferative activity against four human carcinoma cell lines, A549, Bel-7402, MCF-7, and Eca-109, with the lowest IC50 values of 0.33 (10), 0.66 (6), 0.37 (7), and 1.05 (7) μM, respectively. The spectrophotometric results reveal that the compounds have strong affinity binding with DNA as intercalator and induce DNA conformational transition. Molecular docking studies indicate that the binding is contributed by the π…π stacking and hydrogen bonds, providing an order of nucleotide sequence binding selectivity as ATGC > ATAT > GCGC. These compounds intercalate into the base pairs of the DNA of the tumor cells to affect their replication and transcription, and the process is supposed to play an important role in the anticancer mechanism.

DNA Damage Signals Induction of Fas Ligand in Tumor Cells

1999 ◽  
Vol 55 (2) ◽  
pp. 216-222 ◽  
Author(s):  
Yin-Yuan Mo ◽  
William T. Beck
Keyword(s):  
Dna Damage ◽  
Tumor Cells ◽  
Fas Ligand

scholarly journals Xanthohumol, a Prenylated Flavonoid from Hops, Induces DNA Damages in Colorectal Cancer Cells and Sensitizes SW480 Cells to the SN38 Chemotherapeutic Agent

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 932
Author(s):  
Alessandra Scagliarini ◽  
Aline Mathey ◽  
Virginie Aires ◽  
Dominique Delmas
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Anticancer Agents ◽  
Ataxia Telangiectasia Mutated ◽  
Anticancer Compounds ◽  
Dna Damages ◽  
Systematic Screening ◽  
Colorectal Cancer Cells ◽  
Ic50 Values ◽  
First Time

In spite of chemotherapy and systematic screening for people at risk, the mortality rate of colorectal cancer (CRC) remains consistently high, with 600,000 deaths per year. This low success rate in the treatment of CRC results from many failures associated with high resistance and the risk of metastasis. Therefore, in response to these therapeutic failures, new strategies have been under development for several years aimed at increasing the effect of anticancer compounds and/or at reducing their secondary effects on normal cells, thus enabling the host to better withstand chemotherapy. This study highlights that xanthohumol (Xn) concentrations under the IC50 values were able to induce apoptosis and to enhance the DNA-damage response (DDR). We demonstrate for the first time that Xn exerts its anticancer activity in models of colon cancer through activation of the ataxia telangiectasia mutated (ATM) pathway. Subsequently, the ability of Xn to restore DNA damage in CRC cells can sensitize them to anticancer agents such as SN38 (7-ethyl-10-hydroxycamptothecin) used in chemotherapy.

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