Antigenotoxic Activity Research Articles

The antigenotoxic potential of dietary flavonoids

Human exposure to genotoxic agents has dramatically increased. Both endogenous (reactive species generated during physiological and pathological processes) and exogenous (UV light, ionizing radiation, alkylating agents, antimetabolites and topoisomerase inhibitors, air, water and food pollutants) factors can impair genomic stability. The cumulative DNA damage causes mutations involved in the development of cancer and other disorders (neuromuscular and neurodegenerative diseases, immune deficiencies, infertility, cardiovascular diseases, metabolic syndrome and aging). Dietary flavonoids have protective effects against DNA damage induced by different genotoxic agents such as mycotoxins, food processing-derived contaminants (polycyclic aromatic hydrocarbons, N-nitrosamines), cytostatic agents, other medications (estrogenic and androgenic hormones), nicotine, metal ions (Cd2+, Cr6+), radiopharmaceuticals and ionizing radiation. Dietary flavonoids exert their genoprotection by reducing oxidative stress and modulation of enzymes responsible for bioactivation of genotoxic agents and detoxification of their reactive metabolites. Data on structure–activity relationship is sometimes contradictory. Free hydroxyl groups on the B ring (catechol moiety) and C-3 position of the C ring are important structural features for the antigenotoxic activity. As dietary flavonoids are extensively metabolized, more in vivo studies are needed for a better characterization of their antigenotoxic potential.

Protective effects of acerola juice on genotoxicity induced by iron in vivo.

Metal ions such as iron can induce DNA damage by inducing reactive oxygen species (ROS) and oxidative stress. Vitamin C is one of the most widely consumed antioxidants worldwide, present in many fruits and vegetables, especially inMalpighia glabra L., popularly known as acerola, native to Brazil. Acerola is considered a functional fruit due to its high antioxidant properties and phenolic contents, and therefore is consumed to prevent diseases or as adjuvant in treatment strategies. Here, the influence of ripe and unripe acerola juices on iron genotoxicity was analyzed in vivo using the comet assay and micronucleus test. The comet assay results showed that acerola juice exerted no genotoxic or antigenotoxic activity. Neither ripe nor unripe acerola juices were mutagenic to animals treated with juices, in micronucleus test. However, when compared to iron group, the pre-treatment with acerola juices exerted antimutagenic activity, decreasing significantly micronucleus mean values in bone marrow. Stage of ripeness did not influence the interaction of acerola compounds with DNA, and both ripe and unripe acerola juices exerted protective effect over DNA damage generated by iron.

Chemical and biological fingerprints of two Fabaceae species (Cytisopsis dorycniifolia and Ebenus hirsuta): Are they novel sources of natural agents for pharmaceutical and food formulations?

In the present study, the methanolic extracts of Cytisopsis dorycniifolia and Ebenus hirsuta were analyzed for antioxidant, enzyme inhibitory, antimicrobial and antigenotoxic activities. The identification and quantification of phenolic compounds in these extracts were performed using liquid chromatography coupled with mass spectrometry (LC–MS/MS) technique, and the main components were hyperoside, rutin, hesperidin, tannic acid and p-coumaric acid. The extracts had remarkable biological effects. Generally, C. dorycniifolia had higher level of bioactive components and exhibited stronger in vitro antioxidant effects than E. hirsuta. E. hirsuta was active especially against bacteria Pseudomonas fluorescens and Agrobacterium tumefaciens and fungi Puncturella fastigiata, while C. dorycniifolia was active against bacteria E. faecalis and had moderate activity against Trichoderma species. The extracts displayed strong antigenotoxic effects (98.6% for E. hirsuta and 76.3% for C. dorycniifolia). Our findings suggested that C. dorycniifolia and E. hirsuta could be beneficial for the preparation of high-value pharmaceuticals and functional food ingredients.

Cancer Prevention and Health Benefices of Traditionally Consumed Borago officinalis Plants.

Nowadays, healthy eating is increasing the demand of functional foods by societies as sources of bioactive products with healthy qualities. For this reason, we tested the safety of the consumption of Borago officinalis L. and its main phenolic components as well as the possibility of its use as a nutraceutical plant to help in cancer prevention. The in vivo Drosophila Somatic Mutation and Recombination Test (SMART) and in vitro HL-60 human cell systems were performed, as well-recognized methods for testing genotoxicity/cytotoxicity of bioactive compounds and plant products. B. officinalis and the tested compounds possess antigenotoxic activity. Moreover, B. officinalis wild type cultivar exerts the most antigenotoxic values. Cytotoxic effect was probed for both cultivars with IC50 values of 0.49 and 0.28 mg·mL−1 for wild type and cultivated plants respectively, as well as their constituent rosmarinic acid and the assayed phenolic mixture (IC50 = 0.07 and 0.04 mM respectively). B. officinalis exerts DNA protection and anticarcinogenic effects as do its component rosmarinic acid and the mixture of the main phenolics presented in the plant. In conclusion, the results showed that B. officinalis may represent a high value plant for pleiotropic uses and support its consumption as a nutraceutical plant.

Evaluation of genotoxic and antigenotoxic effects of boron by the somatic mutation and recombination test (SMART) on Drosophila

Objective: In this study, different concentrations of boron have been evaluated for genotoxic and antigenotoxic properties by using the somatic mutation and recombination test (SMART) on Drosophila melanogaster. Study Design: The treatment concentrations were chosen to a pretest. Third-instar larvae trans-heterozygous for two genetic markers, multiple wing hair (mwh) and flare (flr3), were treated at different concentrations (0.1, 5, 10, 20, and 40 mg/mL) of boron. In addition to investigating antigenotoxic effects, the same boron concentrations were co-administered with 0.1 mM Ethyl Methane Sulfonate (EMS). Distilled water was used as a negative control; 0.1 mM of EMS was used as a positive control. For the chronic feeding study, small plastic vials were prepared with 1.5 g of dry Drosophila Instant Medium and 5 mL of the respective test solution. Hundreds of trans-heterozygous larvae were embedded into this medium. Feeding ended with pupation of the surviving larvae. After metamorphosis, all surviving flies were collected and stored in a 70% ethanol solution. Preparation and microscopic analyses of wing were made after the treatment. Then the observed mutations were classified according to size and type of mutation per wing. Results: Results indicated that there is no significant genotoxic effect with all of the boron concentrations. In addition, the antigenotoxic activities of boron against EMS were tested. Results indicated that all boron concentrations (0.1, 5, 10, 20 and 40 mg/mL) were able to abolish the genotoxic effects induced by the EMS. Conclusion: It is suggested that the observed effects can be linked to the antioxidant properties of boron. Moreover, these in vivo results will contribute to the antigenotoxicity database of boron.

Antigenotoxic and apoptotic activities of essential oil of Atalantia monophylla Correa.

Objective:To study antigenotoxic and apoptotic activities of hydrodistilled essential oil from the leaves of Atalantia monophylla Correa.Materials and Methods:Antigenotoxic activity of essential oil was tested against hydrogen peroxide (100 μM)-induced deoxyribonucleic acid (DNA) damage in 3T3-L1 cells. Cervical cancer cell (HeLa) growth inhibitory effect of essential oil was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay. Annexin V-fluorescein isothiocyanate/propidium iodide (FITC/PI), Hoechst 33258, and acridine orange/ethidium bromide (AO/EtBr) staining techniques were used to identify apoptosis.Results:DNA protecting the activity of A. monophylla essential oil was high at 125 μg/mL. HeLa cell growth was inhibited dose-dependently and inhibitory concentration 50% was calculated as 43.08 ± 0.02 μg/mL. Annexin V-FITC/PI double staining showed membrane breakage and nuclei staining. Further, Hoechst 33258 and AO/EtBr stain also confirmed the apoptosis in essential oil-treated HeLa cells.Conclusion:The results obtained suggest that A. monophylla essential oil is a promising natural agent which may be used in preparation of herbal medicine to treat cancer and other diseases.

Evaluation of genotoxic and antigenotoxic properties of essential oils of Seseli rigidum Waldst. & Kit. (Apiaceae)

The essential oils of genus Seseli are known for their beneficial biological activities and could present novel targets in the development of safe and effective preparations of plant products. The objective was to test the essential oils of different parts of Seseli rigidum from two natural habitats for potential genotoxic and antigenotoxic activities against H202-induced DNA damage in human whole blood cells in vitro, by the comet assay. The essential oil analysis showed a high falcarinol content in oil from the root, while oils of the fruit and aerial parts contained ?-pinene as the main compound. Genotoxicity was not detected at any of the concentrations of the essential oils from the three parts of the plant from localities I and II. Although the antioxidant activity (established by the FRAP and DPPH tests) of the investigated oils was low, all oils demonstrated a strong antigenotoxic effect against H2O2-induced damage post-treatment, when the oils were applied after the oxidant. Based on the lack of pretreatment activity and the post-treatment reduction in DNA damage, the antigenotoxic effect of S. rigidum essential oils was probably based on the stimulation of DNA repair mechanisms. Environmental conditions did not affect the antigenotoxic properties of the oils. In conclusion, our results revealed the antigenotoxic properties of S. rigidum essential oils and appropriate and safe doses with beneficial effects under the described conditions.

Antigenotoxic and Antioxidant Activity of Lichens Anaptychia ciliaris, Bryoria fuscescens, Parmotrema chinensa and Xanthoria candelaria: An in vitro Study

The protective role of lichens are getting more important. In this study, the antigenotoxic and antimutagenic activity of the methanol extracts of four lichen species (Anaptychia ciliaris, Bryoria fuscescens, Parmotrema chinensa and Xanthoria candelaria) were investigated. Sister Chromatid Exchange (SCE) test were used for determining the genotoxic contamination and the results showed that four lichen extracts inhibited the mutagenic effects of AFB1. Three different concentrations used and it was determined that the most effective concentration is 20 μg/mL againts the mutagenic effects of AFB1. In addition, the antioxidant effects of A. ciliaris, B. fuscescens, P. chinensa and X. candelaria were determined by measuring the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione (GSH) and level of malondialdehyde (MDA) against the oxidative stress of AFB1 in human lymphocytes in vitro. It was observed that the levels of antioxidant enzymes were decreased dramatically and level of malondialdehyde (MDA) increased after treatment with AFB1 but the antioxidant enzymes were increased and MDA levels decreased in case of applying the lichen methanol extracts. We also determined that our lichen samples have strong antioxidative and antigenotoxic character and their antigenotoxic quality may be relation to the mechanisms of strong antioxidative property.

Acylated Triterpene Saponins from the Stem Bark of Acer nikoense (Aceraceae).

Three new acylated triterpene saponins, acernikoenosides A-C (1-3), were isolated from the stem bark of Acer nikoense, together with a known sterol glucoside. Their structures were elucidated on the basis of extensive spectroscopic analyses. This study provided the first example of triterpene saponins isolated from this plant. The anti-genotoxic activity of 1, 3 and 4 against ultraviolet irradiation was evaluated by comet assay.

Protective effects of Dioscorea membranacea rhizome ethanolic extract against doxorubicin-induced genotoxicity in human lymphocytes in vitro

Dioscorea membranacea rhizome is commonly used as an ingredient in traditional Thai remedies for inflammatory diseases and cancers. Our previous study reported that the ethanolic extract of Dioscorea membranacea rhizome (EEDM) was selectively cytotoxic to lung and breast cancer cell lines [1]. However, the underlying mechanisms of its action are still unclear. One possible mechanism might be their anti-genotoxic activities. To investigate the anti-genotoxic potential of the EEDM, in vitro chromosome aberration assay was conducted, testing EEDM against doxorubicin (DXR), a potent genotoxic compound. Genotoxicity indicated by chromatid-type and chromosome-type aberrations and cytotoxicity as shown by mitotic index were analyzed. Human lymphocytes were pretreated with various concentrations of EEDM (0.005 – 50 ng/ml) followed by 0.1 µg/mL DXR. Plain RPMI and DXR were used as negative and positive controls, respectively. The results demonstrated that EEDM pretreatment at 0.5 ng/ml significantly decreased DXR-induced chromatid-type aberrations by a factor of 4.8. Other EEDM pretreatments at 0.05 and 5 ng/ml also tended to decrease DXR-induced chromatid-type aberrations, although they were not statistically significant. Chromosome-type aberration and cytotoxicity was not detected at all EEDM pretreatments. The outcomes revealed that in vitro EEDM pretreatment at a specific dose has anti-genotoxic properties against genotoxic hazards such as DXR in human cells. Therefore, EEDM might be useful not only for anti-cancer treatment but also for cancer prevention. Further in vivo anti-genotoxic studies are needed to confirm this in vitro results.

Antigenotoxic and antioxidant activities of a polyphenolic extract from European Dracocephalum moldavica L.

The aim of the present study was to investigate the antigenotoxic and antioxidant activities of the crude hydromethanolic extract from the aerial parts of European Dracocephalum moldavica L. (Moldavian dragonhead). The total phenolic content estimated by the Folin–Ciocalteu assay was 289.55±2.63mg of GAE/g of dry extract, and rosmarinic acid was the major polyphenol of Dracocephalum moldavica extract (107.11±0.83mg/g of dry extract). In vitro antioxidant assays revelead remarkable scavenging effects against DPPH (EC50=23.10±0.10μg/mL), ABTS (EC50=8.0±0.10μg/mL) and superoxide anion radicals (EC50=445.5±2.3μg/mL). The extract showed a high ferrous ion chelating activity (EC50=35.70±0.40μg/mL), a considerable reducing capacity, and good hydroxyl radical scavenging properties. Dracocephalum moldavica extract reduced, in a concentration-dependent manner, DNA damage induced by bleomycin in normal human dermal fibroblasts as measured by comet assay and micronucleus test. Exposure of dermal fibroblasts to Dracocephalum moldavica extract (100μg/mL) after preincubation with bleomycin (10μg/mL) resulted in the most significant antigenotoxic activity. The protective effects may be due to the free radical scavenging activity, iron-chelating properties and the possible intervention on DNA repair processes.

Genoprotective and neuroprotective effects of Daphne gnidium leaf methanol extract, tested on male mice

Methanol extract of Daphne gnidium leaves was assessed for its antigenotoxic and neuroprotective effects through antioxidant and antibutyrylcholinesterase activities. Antigenotoxic activity was evaluated against methyl methanesulfonate injected intraperitoneally to mice, using the comet assay. The protective effect of D. gnidium reached 99.12%, at the lowest tested dose (44 mg/kg b.w.) in kidney cells, and 92.16% at the dose of 88 mg/kg b.w. in blood cells. The extract was dissolved in water and administrated to mice by intraperitoneal injection. Antioxidant activity was tested against DPPH radicals. It reached a maximum of 74.52% with an IC50 value of 45 µg/ml. Anticholinesterase activity was determined against butyrylcholinesterase, an enzyme linked to Alzheimer disease. The extract exhibited antibutyrylcholinestrase effect with an inhibition percentage of 35.82% at the lowest tested dose (44 mg/kg b.w.).

Energetics, Thermodynamics, and Molecular Recognition of Piperine with DNA.

Piperine, the bioactive phytochemical from black pepper (Piper nigrum L.), is a nontoxic natural compound exhibiting many physiological and pharmacological properties. They include antioxidant, anti-inflammatory, antimutagenic, antitumor, antiapoptotic, antigenotoxic, antiarthritic, antifungal, antimicrobial, antidepressant, anti-HBV, and gastro-protective activities. It also enhances the bioavailability of phytochemicals and drugs. The molecular mechanism of action of piperine with DNA has not yet been addressed, while its pharmacological activities have been reported. In this work we report for the first time the interaction of piperine molecule with DNA duplex. We have carried out UV-vis absorption and fluorescence spectroscopy to confirm the binding of piperine with calf thymus DNA (ctDNA). The energetics of interaction of piperine with ctDNA was monitored by isothermal titration calorimetry (ITC). Differential scanning calorimetry (DSC) and melting temperature (Tm) analysis were also performed, confirming a minor groove mode of binding of piperine with ctDNA. The binding free energy ΔG values obtained from molecular dynamics simulation studies agree well with ITC values and reveal a sequence dependent minor groove binding exhibiting a specificity toward AT rich sequences.

Genotoxicity and Cytotoxicity Evaluation of the Neolignan Analogue 2-(4-Nitrophenoxy)-1Phenylethanone and its Protective Effect Against DNA Damage.

Neolignans are secondary metabolites found in various groups of Angiosperms. They belong to a class of natural compounds with great diversity of chemical structures and pharmacological activities. These compounds are formed by linking two phenylpropanoid units. Several compounds that have ability to prevent genetic damage have been isolated from plants, and can be used to prevent or delay the development of tumor cells. Genetic toxicology evaluation is widely used in risk assessment of new drugs in preclinical screening tests. In this study, we evaluated the genotoxicity and cytotoxicity of the neolignan analogue 2-(4-nitrophenoxy)-1-phenylethanone (4NF) and its protective effect against DNA damage using the mouse bone marrow micronucleus test and the comet assay in mouse peripheral blood. Our results showed that this neolignan analogue had no genotoxic activity and was able to reduce induced damage both in mouse bone marrow and peripheral blood. Although the neolignan analogue 4NF was cytotoxic, it reduced cyclophosphamide-induced cytotoxicity. In conclusion, it showed no genotoxic action, but exhibited cytotoxic, antigenotoxic, and anticytotoxic activities.

Comparative study of genotoxic, antigenotoxic and cytotoxic activities of monoterpenes camphor, eucalyptol and thujone in bacteria and mammalian cells

Genotoxic/antigenotoxic, mutagenic/antimutagenic and cytotoxic effects of monoterpenes camphor, eucalyptol and thujone were determined in bacteria and mammalian cells using alkaline comet assay, Escherichia coli K12 reversion test and MTT assay, respectively. When applied in low doses (up to 200 μM in bacterial assay and 50 μM in comet assay) monoterpenes protected repair proficient E. coli and Vero cells against UV-induced mutagenesis and 4NQO-induced DNA strand breaks, respectively. Antimutagenic response was not detected in nucleotide excision repair (NER) deficient bacteria. When monoterpenes were applied in higher doses, a weak mutagenic effect was found in mismatch repair (MMR) and NER deficient E. coli strains, while induction of DNA strand breaks was evident in human fetal lung fibroblasts MRC-5, colorectal carcinoma HT-29 and HCT 116 cells, as well as in Vero cells. Moreover, the involvement of NER, MMR and RecBCD pathways in repair of DNA lesions induced by monoterpenes was demonstrated in E. coli. Camphor, eucalyptol and thujone were cytotoxic to MRC-5, HT-29 and HCT 116 cells. The most susceptible cell line was HCT 116, with IC50 values of 4.5 mM for camphor, 4 mM for eucalyptol and 1 mM for thujone. Observed effects of monoterpenes are consistent with hormesis response, characterized by a low dose beneficial effect and a high dose adverse effect of a stressor agent, and provide a basis for further study of both chemopreventive and chemotherapeutic potential of camphor, eucalyptol and thujone.

Antigenotoxic, anti-photogenotoxic and antioxidant activities of natural naphthoquinone shikonin and acetylshikonin and Arnebia euchroma callus extracts evaluated by the umu-test and EPR method

The aim of this study was to evaluate the antigenotoxic and antioxidant potential of shikonin (SH), acetylshikonin (ACS) and Arnebia euchroma callus extract (EXT). The antigenotoxic activity was investigated by the umu-test as the inhibition of the SOS system induction caused by genotoxic chemical agents — 4-nitroquinoline oxide and 2-aminoanthracene. Moreover the ability of SH, ACS and EXT to prevent photogenotoxicity triggered by chlorpromazine under UVA irradiation was measured. The cytotoxicity of EXT toward V79 Chinese hamster cell line was additionally assessed. Shikonin and acetylshikonin had no effect on 4-NQO induced genotoxicity whereas EXT demonstrated an unclear effect. The protection against 2AA induced genotoxicity was observed for all tested substances. The highest protection was demonstrated for EXT with inhibition of 66%. SH and ACS reduced 2AA genotoxicity with inhibition of about 60%. Under UVA the strongest and dose-dependent activity was observed for EXT. Acetylshikonin was a weak anti-photogenotoxin whereas shikonin had no clear effect. EXT was highly cytotoxic toward the V79 cell line — the cells' morphology was affected seriously and apoptosis was impacted.The antioxidant activity of SH, ACS and EXT was studied by means of electron paramagnetic resonance spectroscopy using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. All three samples exhibited radical scavenging properties.

Antigenotoxic activity of lactic acid bacteria, prebiotics, and products of their fermentation against selected mutagens

Dietary components such as lactic acid bacteria (LAB) and prebiotics can modulate the intestinal microbiota and are thought to be involved in the reduction of colorectal cancer risk. The presented study measured, using the comet assay, the antigenotoxic activity of both probiotic and non-probiotic LAB, as well as some prebiotics and the end-products of their fermentation, against fecal water (FW). The production of short chain fatty acids by the bacteria was quantified using HPLC. Seven out of the ten tested viable strains significantly decreased DNA damage induced by FW. The most effective of them were Lactobacillus mucosae 0988 and Bifidobacterium animalis ssp. lactis Bb-12, leading to a 76% and 80% decrease in genotoxicity, respectively. The end-products of fermentation of seven prebiotics by Lactobacillus casei DN 114-001 exhibited the strongest antigenotoxic activity against FW, with fermented inulin reducing genotoxicity by 75%. Among the tested bacteria, this strain produced the highest amounts of butyrate in the process of prebiotic fermentation, and especially from resistant dextrin (4.09 μM/mL). Fermented resistant dextrin improved DNA repair by 78% in cells pre-treated with 6.8 μM methylnitronitrosoguanidine (MNNG). Fermented inulin induced stronger DNA repair in cells pre-treated with mutagens (FW, 25 μM hydrogen peroxide, or MNNG) than non-fermented inulin, and the efficiency of DNA repair after 120 min of incubation decreased by 71%, 50% and 70%, respectively. The different degrees of genotoxicity inhibition observed for the various combinations of bacteria and prebiotics suggest that this effect may be attributable to carbohydrate type, SCFA yield, and the ratio of the end-products of prebiotic fermentation.

Genotoxic, Cytotoxic, Antigenotoxic, and Anticytotoxic Effects of Sulfonamide Chalcone Using the Ames Test and the Mouse Bone Marrow Micronucleus Test.

Chalcones present several biological activities and sulfonamide chalcone derivatives have shown important biological applications, including antitumor activity. In this study, genotoxic, cytotoxic, antigenotoxic, and anticytotoxic activities of the sulfonamide chalcone N-{4-[3-(4-nitrophenyl)prop-2-enoyl]phenyl} benzenesulfonamide (CPN) were assessed using the Salmonella typhimurium reverse mutation test (Ames test) and the mouse bone marrow micronucleus test. The results showed that CPN caused a small increase in the number of histidine revertant colonies in S. typhimurium strains TA98 and TA100, but not statistically significant (p > 0.05). The antimutagenicity test showed that CPN significantly decreased the number of His+ revertants in strain TA98 at all doses tested (p < 0.05), whereas in strain TA100 this occurred only at doses higher than 50 μg/plate (p < 0.05). The results of the micronucleus test indicated that CPN significantly increased the frequency of micronucleated polychromatic erythrocytes (MNPCE) at 24 h and 48 h, revealing a genotoxic effect of this compound. Also, a significant decrease in polychromatic/normochromatic erythrocyte ratio (PCE/NCE) was observed at the higher doses of CPN at 24 h and 48 h (p < 0.05), indicating its cytotoxic action. CPN co-administered with mitomycin C (MMC) significantly decreased the frequency of MNPCE at almost all doses tested at 24 h (p < 0.05), showing its antigenotoxic activity, and also presented a small decrease in MNPCE at 48 h (p > 0.05). Additionally, CPN co-administered with MMC significantly increased PCE/NCE ratio at all doses tested, demonstrating its anticytotoxic effect. In summary, CPN presented genotoxic, cytotoxic, antigenotoxic, and anticytotoxic properties.

Biological and Health-promoting Activity of Vinification Byproducts Produced in Spanish Vineyards

Several by-products are produced in the Spanish agricultural system. Among them, fresh and vinified grape skins represent an abundant source of phenols with a potential nutraceutical value. Fresh grape skin extracts (FGSE) and vinification of grape skin extracts (VGSE) obtained by a microwave-assisted method have been chemically and biologically characterised. Their role in the maintenance of genetic stability was stated by in vivo genotoxic and antigenotoxic evaluations (Drosophilla melanogaster wing spot test), as well as by their potential chemopreventive effect (in an HL60 in vitro model). Total phenolic, anthocyanin and resveratrol contents were chemically characterised in the two extracts, showing some qualitative differences. Both extracts and resveratrol were not mutagenic in the Drosophila somatic mutation and recombination tests, and exerted antigenotoxic activities against hydrogen peroxide. They also showed cytotoxic activity to HL60 leukaemia cells, with an IC 50 of 4.5µL/mL, 4.6µL/mL and 98µM respectively and induced apoptotic internucleosomic fragmentation in the HL60 cell line.

Newly discovered chroman-2,4-diones neutralize the in vivo DNA damage induced by alkylation through the inhibition of Topoisomerase IIα: A story behind the molecular modeling approach

Eight chroman-2,4-diones, namely 2a–h, previously investigated as anticoagulants, of which 2a and 2f as the most active, were evaluated as in vivo genotoxic agents in Wistar rat livers and kidneys using the comet assay. Compounds 2a, 2b, and 2f without genotoxic activity were applied prior to ethyl methanesulfonate (EMS) and diminished EMS-induced DNA damage according to the total score and percentage of reduction. EMS produce harmful O6-ethylguanine lesion which is incorporated in aberrant genotoxic GT and TG pairing after ATP-dependent DNA strand breaks have been catalyzed by rat Topoisomerase IIα (rTopIIα, EC 5.99.1.3). Therefore, the mechanism of 2a, 2b, and 2f antigenotoxic activity was investigated on the enzyme level using molecular docking and molecular dynamics simulations insamuch as it had been determined that compounds do not intercalate DNA but instead inhibit the ATPase activity. Calculations predicted that compounds inhibit ATP hydrolysis before the DNA–EMS cleavage is being catalyzed by rTopIIα, prevent EMS mutagenic and carcinogenic effects, and beside anticoagulant activity can even be applied in the cancer treatment to control the rate of anticancer alkylation drugs.