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Proceedings of the National Academy of... Jul 2023Type II topoisomerases transiently cleave duplex DNA as part of a strand passage mechanism that helps control chromosomal organization and superstructure. Aberrant DNA...
Type II topoisomerases transiently cleave duplex DNA as part of a strand passage mechanism that helps control chromosomal organization and superstructure. Aberrant DNA cleavage can result in genomic instability, and how topoisomerase activity is controlled to prevent unwanted breaks is poorly understood. Using a genetic screen, we identified mutations in the beta isoform of human topoisomerase II (hTOP2β) that render the enzyme hypersensitive to the chemotherapeutic agent etoposide. Several of these variants were unexpectedly found to display hypercleavage behavior in vitro and to be capable of inducing cell lethality in a DNA repair-deficient background; surprisingly, a subset of these mutations were also observed in sequences from cancer genome databases. Using molecular dynamics simulations and computational network analyses, we found that many of the mutations obtained from the screen map to interfacial points between structurally coupled elements, and that dynamical modeling could be used to identify other damage-inducing alleles present in cancer genome databases. This work establishes that there is an innate link between DNA cleavage predisposition and sensitivity to topoisomerase II poisons, and that certain sequence variants of human type II topoisomerases found in cancer cells can act as DNA-damaging agents. Our findings underscore the potential for hTOP2β to function as a clastogen capable of generating DNA damage that may promote or support cellular transformation.
Topics: Humans; Mutagens; Topoisomerase II Inhibitors; Etoposide; DNA Topoisomerases, Type II; DNA Damage; DNA; Neoplasms
PubMed: 37406101
DOI: 10.1073/pnas.2302064120 -
Strahlentherapie Und Onkologie : Organ... Sep 2022To evaluate the mutagen sensitivity phenotype on the risk of second primary cancer (SPC) in patients with head and neck squamous cell carcinoma (HNSCC), and to estimate...
PURPOSE
To evaluate the mutagen sensitivity phenotype on the risk of second primary cancer (SPC) in patients with head and neck squamous cell carcinoma (HNSCC), and to estimate the long-term rate of SPC and the outcome with SPC.
METHODS
A survey was made regarding SPC among 124 younger (≤ 50 years) adults with HNSCC who were enrolled in a pretreatment mutagen sensitivity investigation during 1996-2006. Mutagen sensitivity was assessed by exposing lymphocytes to bleomycin in vitro and quantifying the bleomycin-induced chromatid breaks per cell (b/c). Patients were classified as hypersensitive (> 1 b/c) or not hypersensitive (≤ 1 b/c).
RESULTS
Mean follow-up time for all patients was 68 months (range: 5-288 months), and the 15-year cancer-specific survival was 15%. Twenty patients (16%) developed a SPC (15-year estimated rate: 41%), and half of them was hypersensitive. The crude rate of SPC for hypersensitive (n = 65) or not hypersensitive (n = 59) patients were 15 and 17%, respectively (p = 0.4272). The 15-year estimated rate of SPC for hypersensitive and not hypersensitive patients was 36 and 48%, respectively (p = 0.3743). Gender, UICC stages, anatomical sites of index cancer did not prove to be a significant risk factor for SPC. Forty-five percent of SPC developed after the 10-year follow-up. The 3‑year cancer-specific survival was 23% with SPC.
CONCLUSION
According to our findings, mutagen hypersensitivity was not associated with an increased SPC risk in HNSCC patients. Patients are at a lifelong risk of developing a SPC. Survival with SPC is very poor.
Topics: Bleomycin; Carcinoma, Squamous Cell; Epithelial Cells; Head and Neck Neoplasms; Humans; Mutagens; Neoplasms, Second Primary; Squamous Cell Carcinoma of Head and Neck
PubMed: 35357513
DOI: 10.1007/s00066-022-01917-2 -
Biomolecules May 2020Spironolactone (SP) is commonly used for the treatment of heart failure, hypertension, and complications of cirrhosis by antagonizing the mineralocorticoid receptor.... (Review)
Review
Spironolactone (SP) is commonly used for the treatment of heart failure, hypertension, and complications of cirrhosis by antagonizing the mineralocorticoid receptor. However, SP also antagonizes the androgen receptor, and thus SP has also been shown to be effective in the treatment of acne, hair loss, and hirsutism in women. Interestingly, recent drug repurposing screens have identified new and diverse functions for SP as a simulator of tumor immunosurveillance and as an inhibitor of DNA repair and viral infection. These novel pharmacological effects of SP have all been linked to the ability of SP to induce the rapid proteolytic degradation of the xeroderma pigmentosum group B (XPB) protein. XPB is a critical enzymatic component of the multi-subunit complex known as transcription factor II-H (TFIIH), which plays essential roles in both DNA repair and the initiation of transcription. Given the critical functions for XPB and TFIIH in these processes, the loss of XPB by SP could lead to mutagenesis. However, the ability of SP to promote cancer stem cell death and facilitate immune recognition may counteract the negative consequences of SP to mitigate carcinogenic risk. Thus, SP appears to have new and interesting pharmacological effects that may extend its potential uses.
Topics: Animals; Carcinogens; DNA Helicases; DNA Repair; DNA-Binding Proteins; Humans; Mutagens; Proteolysis; Spironolactone
PubMed: 32414008
DOI: 10.3390/biom10050756 -
Medycyna Pracy Jul 2019The drawing up of a new regulation of the Minister of Family, Labour and Social Policy regarding the maximum admissible concentrations and intensities of agents harmful... (Review)
Review
The drawing up of a new regulation of the Minister of Family, Labour and Social Policy regarding the maximum admissible concentrations and intensities of agents harmful to health in the working environment resulted from the obligatory implementation into national law the provisions of Commission Directive (EU) 2017/164 of 31 January 2017 establishing a fourth list of indicative occupational exposure limit values pursuant to Council Directive 98/24/EC, and amending Commission Directives 91/322/EEC, 2000/39/EC and 2009/161/EU, the provisions of which Member States had to introduce by 21 August 2018, and partly Directive 2017/2398/EU of the European Parliament and of the Council of 12 December 2017 amending Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens or mutagens at work. The Regulation takes into account 13 applications submitted in the years 2014-2017 by the Interdepartmental Commission for Maximum Admissible Concentrations and Intensities for Agents Harmful to Health in the Working Environment to the minister competent for labour issues. The Commission was appointed by way of the regulation of the Prime Minister of 15 December 2008 (Journal of Laws 2015, item 1772, as amended), and its tasks include submitting to the minister competent for labour issues applications regarding the value of the maximum admissible concentrations and intensities for agents harmful to health in the working environment. Med Pr. 2019;70(4):497-509.
Topics: Carcinogens; European Union; Humans; Mutagens; Occupational Exposure; Occupational Health
PubMed: 31241622
DOI: 10.13075/mp.5893.00832 -
Regulatory Toxicology and Pharmacology... Dec 2022Titanium dioxide is a ubiquitous white material found in a diverse range of products from foods to sunscreens, as a pigment and thickener, amongst other uses. Titanium... (Review)
Review
Titanium dioxide is a ubiquitous white material found in a diverse range of products from foods to sunscreens, as a pigment and thickener, amongst other uses. Titanium dioxide has been considered no longer safe for use in foods (nano and microparticles of E171) by the European Food Safety Authority (EFSA) due to concerns over genotoxicity. There are however, conflicting opinions regarding the safety of Titanium dioxide. In an attempt to clarify the situation, a comprehensive weight of evidence (WoE) assessment of the genotoxicity of titanium dioxide based on the available data was performed. A total of 192 datasets for endpoints and test systems considered the most relevant for identifying mutagenic and carcinogenic potential were reviewed and discussed for both reliability and relevance (by weight of evidence) and in the context of whether the physico-chemical properties of the particles had been characterised. The view of an independent panel of experts was that, of the 192 datasets identified, only 34 met the reliability and quality criteria for being most relevant in the evaluation of genotoxicity. Of these, 10 were positive (i.e. reported evidence that titanium dioxide was genotoxic), all of which were from studies of DNA strand breakage (comet assay) or chromosome damage (micronucleus or chromosome aberration assays). All the positive findings were associated with high cytotoxicity, oxidative stress, inflammation, apoptosis, necrosis, or combinations of these. Considering that DNA and chromosome breakage can be secondary to physiological stress, it is highly likely that the observed genotoxic effects of titanium dioxide, including those with nanoparticles, are secondary to physiological stress. Consistent with this finding, there were no positive results from the in vitro and in vivo gene mutation studies evaluated, although it should be noted that to definitively conclude a lack of mutagenicity, more robust in vitro and in vivo gene mutation studies would be useful. Existing evidence does not therefore support a direct DNA damaging mechanism for titanium dioxide (nano and other forms).
Topics: Reproducibility of Results; Metal Nanoparticles; Titanium; Comet Assay; DNA Damage; Mutagens; DNA
PubMed: 36228836
DOI: 10.1016/j.yrtph.2022.105263 -
Toxins Dec 2022The presence of cyanotoxins and its bioaccumulation in the food chain is an increasingly common problem worldwide. Despite the toxic effects produced by Anatoxin-a... (Review)
Review
The presence of cyanotoxins and its bioaccumulation in the food chain is an increasingly common problem worldwide. Despite the toxic effects produced by Anatoxin-a (ATX-a), this neurotoxin has been less studied compared to microcystins (MCs) and cylindrospermopsin (CYN). Studies conducted under laboratory conditions are of particular interest because these provide information which are directly related to the effects produced by the toxin. Currently, the World Health Organization (WHO) considers the ATX-a toxicological database inadequate to support the publication of a formal guideline reference value. Therefore, the aim of the present work is to compile all of the and toxicological studies performed so far and to identify potential data gaps. Results show that the number of reports is increasing in recent years. However, more studies are needed, mainly in standardized neuronal cell lines. Regarding studies, very few of them reflect conditions occurring in nature and further studies with longer periods of oral exposure would be of interest. Moreover, additional toxicological aspects of great interest such as mutagenicity, genotoxicity, immunotoxicity and alteration of hormonal balance need to be studied in depth.
Topics: Bacterial Toxins; Tropanes; Microcystins; Neurotoxins; Mutagens
PubMed: 36548758
DOI: 10.3390/toxins14120861 -
Regulatory Toxicology and Pharmacology... Oct 2019In silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such methods is increasing in all applications but especially for regulatory...
In silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such methods is increasing in all applications but especially for regulatory submissions, such as for assessing chemicals under REACH as well as the ICH M7 guideline for drug impurities. There are a number of obstacles to performing an IST assessment, including uncertainty in how such an assessment and associated expert review should be performed or what is fit for purpose, as well as a lack of confidence that the results will be accepted by colleagues, collaborators and regulatory authorities. To address this, a project to develop a series of IST protocols for different hazard endpoints has been initiated and this paper describes the genetic toxicity in silico (GIST) protocol. The protocol outlines a hazard assessment framework including key effects/mechanisms and their relationships to endpoints such as gene mutation and clastogenicity. IST models and data are reviewed that support the assessment of these effects/mechanisms along with defined approaches for combining the information and evaluating the confidence in the assessment. This protocol has been developed through a consortium of toxicologists, computational scientists, and regulatory scientists across several industries to support the implementation and acceptance of in silico approaches.
Topics: Animals; Computer Simulation; Humans; Models, Theoretical; Mutagenicity Tests; Mutagens; Research Design; Risk Assessment; Toxicology
PubMed: 31195068
DOI: 10.1016/j.yrtph.2019.104403 -
International Journal of Molecular... Feb 2020Aristolochic acid (AA) is a generic term that describes a group of structurally related compounds found in the Aristolochiaceae plants family. These plants have been... (Review)
Review
Aristolochic acid (AA) is a generic term that describes a group of structurally related compounds found in the Aristolochiaceae plants family. These plants have been used for decades to treat various diseases. However, the consumption of products derived from plants containing AA has been associated with the development of nephropathy and carcinoma, mainly the upper urothelial carcinoma (UUC). AA has been identified as the causative agent of these pathologies. Several studies on mechanisms of action of AA nephrotoxicity have been conducted, but the comprehensive mechanisms of AA-induced nephrotoxicity and carcinogenesis have not yet fully been elucidated, and therapeutic measures are therefore limited. This review aimed to summarize the molecular mechanisms underlying AA-induced nephrotoxicity with an emphasis on its enzymatic bioactivation, and to discuss some agents and their modes of action to reduce AA nephrotoxicity. By addressing these two aspects, including mechanisms of action of AA nephrotoxicity and protective approaches against the latter, and especially by covering the whole range of these protective agents, this review provides an overview on AA nephrotoxicity. It also reports new knowledge on mechanisms of AA-mediated nephrotoxicity recently published in the literature and provides suggestions for future studies.
Topics: Animals; Aristolochic Acids; Carcinogens; DNA Adducts; Humans; Kidney Neoplasms; Mutagens; Tumor Suppressor Protein p53
PubMed: 32050524
DOI: 10.3390/ijms21031157 -
Ecotoxicology and Environmental Safety Jun 2024This study explores the eco-geno-toxic impact of Acyclovir (ACV), a widely used antiviral drug, on various freshwater organisms, given its increasing detection in...
This study explores the eco-geno-toxic impact of Acyclovir (ACV), a widely used antiviral drug, on various freshwater organisms, given its increasing detection in surface waters. The research focused on non-target organisms, including the green alga Raphidocelis subcapitata, the rotifer Brachionus calyciflorus, the cladoceran crustacean Ceriodaphnia dubia, and the benthic ostracod Heterocypris incongruens, exposed to ACV to assess both acute and chronic toxicity. The results indicate that while acute toxicity occurs at environmentally not-relevant concentrations, a significant chronic toxicity for C. dubia (EC = 0.03 µg/L, NOEC = 0.02·10 µg/L), highlighted substantial environmental concern. Furthermore, DNA strand breaks and reactive oxygen species detected in C. dubia indicate significant increase at concentrations exceeding 200 µg/L. Regarding environmental risk, the authors identified chronic exposures to acyclovir causing inhibitory effects on reproduction in B. calyciflorus at hundreds of µg/L and hundredths of µg/L for C. dubia as environmentally relevant environmental concentrations. The study concludes by quantifying the toxic and genotoxic risks of ACV showing a chronic risk quotient higher than the critical value of 1and a genotoxic risk quotient reaching this threshold, highlighting the urgent need for a broader risk assessment of ACV for its significant implications for aquatic ecosystems.
Topics: Animals; Water Pollutants, Chemical; Fresh Water; Antiviral Agents; Acyclovir; Rotifera; Reactive Oxygen Species; Cladocera; Aquatic Organisms; Toxicity Tests, Acute; DNA Damage; Reproduction; Toxicity Tests, Chronic; Mutagens; Chlorophyta
PubMed: 38718728
DOI: 10.1016/j.ecoenv.2024.116437 -
International Journal of Medical... May 2020In recent years, more and more data indicate the effect of human microbiota on carcinogenesis. Despite the numerous studies on the relationship between gut microbiota... (Review)
Review
In recent years, more and more data indicate the effect of human microbiota on carcinogenesis. Despite the numerous studies on the relationship between gut microbiota and carcinogenesis, the exact mechanisms of this interaction are not well studied. It becomes apparent that this relationship can be mediated by microbial metabolites. Mechanisms of some well-known bacterial genotoxins and oncogenes, such as colibactin, CagA, IpgD, VirA, P37, have been studied in detail. At the same time, a role in carcinogenesis of a large group of gut microbial metabolites, including short-chain fatty acids, polyamines, and products of polyphenol and tryptophan catabolism, is less well understood. However, more and more evidence data show the effect of bacterial metabolites on cancer development and progression. In this review, we summarize relevant data regarding the possible mechanisms that can account for the effects of gut microbial metabolites mentioned above in carcinogenesis.
Topics: Animals; Bacteria; Carcinogenesis; Fatty Acids, Volatile; Gastrointestinal Microbiome; Gastrointestinal Tract; Host Microbial Interactions; Humans; Mice; Mutagens; Oncogenes
PubMed: 32423739
DOI: 10.1016/j.ijmm.2020.151425