RESUMEN
The field of sun protection is quickly changing and the research article by Douki et al., published in the current issue of Photochemistry and Photobiology, reported key experimental data that will certainly help the development of better sun care products. Mutagenic photoproducts (CPDs, cyclobutane pyrimidine dimers and 6-4PPs, pyrimidine-6-4-pyrimidone photoproducts) were formed in the reconstructed human epidermis (RHE) by UVB (312 nm) irradiation, and their concentrations were detected by HPLC-MS/MS as a function of time after the UVB treatment. RHE had been previously exposed or not (control) to blue light (427 nm). Both CPDs and 6-4PPs were shown to last longer in blue-light irradiated RHE, proving the inhibition of the DNA repair by blue light exposure. This is a highly relevant information because sunscreens allow people to enjoy longer periods under the sun and consequently, to endure very high doses of blue light. The work also reported results obtained with RHEs previously treated with a sunscreen formulation containing a broadband filter that offers blue-light protection. Interestingly, authors observed that the DNA repair was not significantly inhibited in RHE previously treated with the sunscreen offering broadband protection. Readers will find a scientifically sound proof of the importance of blue-light protection in sun care products.
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Reparación del ADN , Protectores Solares , Humanos , Reparación del ADN/efectos de los fármacos , Protectores Solares/farmacología , Protectores Solares/química , Piel/efectos de la radiación , Piel/efectos de los fármacos , Luz , Rayos Ultravioleta/efectos adversos , Dímeros de PirimidinaRESUMEN
Type 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing ß-cells leading to impaired insulin secretion and hyperglycemia. T1D is accompanied by DNA damage, oxidative stress, and inflammation, although there is still scarce information about the oxidative stress response and DNA repair in T1D pathogenesis. We used the microarray method to assess mRNA expression profiles in peripheral blood mononuclear cells (PBMCs) of 19 T1D patients compared to 11 controls and identify mRNA targets of microRNAs that were previously reported for T1D patients. We found 277 differentially expressed genes (220 upregulated and 57 downregulated) in T1D patients compared to controls. Analysis by gene sets (GSA and GSEA) showed an upregulation of processes linked to ROS generation, oxidative stress, inflammation, cell death, ER stress, and DNA repair in T1D patients. Besides, genes related to oxidative stress responses and DNA repair (PTGS2, ATF3, FOSB, DUSP1, and TNFAIP3) were found to be targets of four microRNAs (hsa-miR-101, hsa-miR148a, hsa-miR-27b, and hsa-miR-424). The expression levels of these mRNAs and microRNAs were confirmed by qRT-PCR. Therefore, the present study on differential expression profiles indicates relevant biological functions related to oxidative stress response, DNA repair, inflammation, and apoptosis in PBMCs of T1D patients relative to controls. We also report new insights regarding microRNA-mRNA interactions, which may play important roles in the T1D pathogenesis.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , MicroARNs/farmacología , Adolescente , Adulto , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Reparación del ADN/efectos de los fármacos , Reparación del ADN/genética , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Perfilación de la Expresión Génica/métodos , Perfilación de la Expresión Génica/estadística & datos numéricos , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Masculino , MicroARNs/metabolismo , MicroARNs/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Regulación hacia ArribaRESUMEN
Airborne particulate matter with a diameter size of ≤10 µm (PM10) is a carcinogen that contains polycyclic aromatic hydrocarbons (PAH), which form PAH-DNA adducts. However, the way in which these adducts are managed by DNA repair pathways in cells exposed to PM10 has been partially described. We evaluated the effect of PM10 on nucleotide excision repair (NER) activity and on the levels of different proteins of this pathway that eliminate bulky DNA adducts. Our results showed that human lung epithelial cells (A549) exposed to 10 µg/cm2 of PM10 exhibited PAH-DNA adducts as well as an increase in RAD23 and XPD protein levels (first responders in NER). In addition, PM10 increased the levels of H4K20me2, a recruitment signal for XPA. However, we observed a decrease in total and phosphorylated XPA (Ser196) and an increase in phosphatase WIP1, aside from the absence of XPA-RPA complex, which participates in DNA-damage removal. Additionally, an NER activity assay demonstrated inhibition of the NER functionality in cells exposed to PM10, indicating that XPA alterations led to deficiencies in DNA repair. These results demonstrate that PM10 exposure induces an accumulation of DNA damage that is associated with NER inhibition, highlighting the role of PM10 as an important contributor to lung cancer.
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Reparación del ADN/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Pulmón/efectos de los fármacos , Material Particulado/efectos adversos , Proteína de la Xerodermia Pigmentosa del Grupo A/metabolismo , Células A549 , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Células Epiteliales/metabolismo , Humanos , Pulmón/metabolismo , Neoplasias Pulmonares/metabolismoRESUMEN
Millions of people worldwide are exposed to arsenic, a metalloid listed as one of the top chemical pollutants of concern to human health. Epidemiological and experimental studies link arsenic exposure to the development of cancer and other diseases. Several mechanisms have been proposed to explain the effects induced by arsenic. Notably, arsenic and its metabolites interact with proteins by direct binding to individual cysteine residues, cysteine clusters, zinc finger motifs, and RING finger domains. Consequently, arsenic interactions with proteins disrupt the functions of proteins and may lead to the development and progression of diseases. In this review, we focus on current evidence in the literature that implicates the interaction of arsenic with proteins as a mechanism of arsenic toxicity. Data show that arsenic-protein interactions affect multiple cellular processes and alter epigenetic regulation, cause endocrine disruption, inhibit DNA damage repair mechanisms, and deregulate gene expression, among other adverse effects.
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Intoxicación por Arsénico/etiología , Arsenicales/efectos adversos , Disruptores Endocrinos/efectos adversos , Contaminantes Ambientales/efectos adversos , Proteínas/metabolismo , Animales , Intoxicación por Arsénico/genética , Intoxicación por Arsénico/metabolismo , Arsenicales/metabolismo , Cisteína , Reparación del ADN/efectos de los fármacos , Disruptores Endocrinos/metabolismo , Contaminantes Ambientales/metabolismo , Epigénesis Genética/efectos de los fármacos , Humanos , Unión Proteica , Proteínas/genética , Dominios RING Finger , Medición de Riesgo , Dedos de ZincRESUMEN
Mercury (Hg) is one of the most toxic environmental pollutants, especially when methylated, forming methylmercury (MeHg). MeHg affects DNA repair, increases oxidative stress, and predisposes to cancer. MeHg neurotoxicity is well-known, but recently MeHg-associated cardiovascular effects were recognized. This study evaluated circulating lipids, oxidative stress, and genotoxicity after MeHg-chronic exposure (20 mg/L in drinking water) in C57BL/6J wild-type and APOE knockout (ko) mice, the latter, being spontaneously dyslipidemic. Experimental mice were assigned to four groups: non-intoxicated and MeHg-intoxicated wild-type mice and non-intoxicated and MeHg-intoxicated APOE ko mice. Plasma levels of triglycerides, total cholesterol (TC), HDL, and LDL were analyzed. Liver lipid peroxidation and splenic gene expression of xeroderma pigmentosum complementation groups A, C, D, and G (XPA, XPC, XPD, and XPG), X-ray repair cross-complementing protein 1 (XRCC1), and telomerase reverse transcriptase (TERT) were measured. Fur Hg levels confirmed chronic MeHg intoxication. MeHg exposure raises TC levels both in wild-type and APOE ko mice. HDL and LDL-cholesterol levels were increased only in the MeHg-challenged APOE ko mice. MeHg increased liver lipid peroxidation, regardless of the genetic background. Unintoxicated APOE ko mice showed higher expression of TERT than all other groups. APOE deficiency increases XPA expression, regardless of MeHg intoxication. Furthermore, MeHg-intoxicated mice had more cytogenetic abnormalities, effect which was independent of APOE deficiency. More studies are needed to dissect the interactions between circulating lipids, MeHg intoxication, and DNA-repair pathways even at young age, interactions that likely play critical roles in cell senescence and the risk for chronic disorders later in life.
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Aberraciones Cromosómicas/inducido químicamente , Reparación del ADN/efectos de los fármacos , Compuestos de Metilmercurio/toxicidad , Estrés Oxidativo/efectos de los fármacos , Animales , ADN de Cadena Simple/genética , ADN de Cadena Simple/metabolismo , Dislipidemias/metabolismo , Contaminantes Ambientales/toxicidad , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoERESUMEN
The sodium valproate has been largely used as an anti-epilepsy drug and, recently, as a putative drug in cancer therapy. However, the treatment with sodium valproate has some adverse effects. In this sense, more effective and secure complexes than sodium valproate should be explored in searching for new active drugs. This study aims to evaluate the cytotoxicity of sodium valproate, mixed ternary mononuclear Cu(II) complexes based on valproic acid (VA) with 1,10-phenanthroline (Phen) or 2,2'- bipyridine (Bipy) ligands - [Cu2(Valp)4], [Cu(Valp)2Phen] and [Cu(Valp)2Bipy] - in yeast Saccharomyces cerevisiae, proficient or deficient in different repair pathways, such as base excision repair (BER), nucleotide excision repair (NER), translesion synthesis (TLS), DNA postreplication repair (PRR), homologous recombination (HR) and non-homologous end-joining (NHEJ). The results indicated that the Cu(II) complexes have higher cytotoxicity than sodium valproate in the following order: [Cu(Valp)2Phen] > [Cu(Valp)2Bipy] > [Cu2(Valp)4] > sodium valproate. The treatment with Cu(II) complexes and sodium valproate induced mutations in S. cerevisiae. The data indicated that yeast strains deï¬cient in BER (Ogg1p), NER (complex Rad1p-Rad10p) or TLS (Rev1p, Rev3p and Rad30p) proteins are associated with increased sensitivity to sodium valproate. The BER mutants (ogg1Δ, apn1Δ, rad27Δ, ntg1Δ and ntg2Δ) showed increased sensitivity to Cu(II) complexes. DNA damage induced by the complexes requires proteins from NER (Rad1p and Rad10p), TLS (Rev1p, Rev3p and Rad30p), PRR (Rad6 and Rad18p) and HR (Rad52p and Rad50p) for efficient repair. Therefore, Cu(II) complexes display enhanced cytotoxicity when compared to the sodium valproate and induce distinct DNA lesions, indicating a potential application as cytotoxic agents.
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Cobre/farmacología , Reparación del ADN/efectos de los fármacos , Preparaciones Farmacéuticas/administración & dosificación , Fenantrolinas/farmacología , Saccharomyces cerevisiae/efectos de los fármacos , Ácido Valproico/farmacología , ADN/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Ligandos , Mutación/efectos de los fármacos , Recombinación Genética/efectos de los fármacosRESUMEN
BACKGROUND: The advances in colorectal cancer (CRC) treatment include the identification of deficiencies in Mismatch Repair (MMR) pathway to predict the benefit of adjuvant 5-fluorouracil (5-FU) and oxaliplatin for stage II CRC and immunotherapy. Defective MMR contributes to chemoresistance in CRC. A growing body of evidence supports the role of Poly-(ADP-ribose) polymerase (PARP) inhibitors, such as Olaparib, in the treatment of different subsets of cancer beyond the tumors with homologous recombination deficiencies. In this work we evaluated the effect of Olaparib on 5-FU cytotoxicity in MMR-deficient and proficient CRC cells and the mechanisms involved. METHODS: Human colon cancer cell lines, proficient (HT29) and deficient (HCT116) in MMR, were treated with 5-FU and Olaparib. Cytotoxicity was assessed by MTT and clonogenic assays, apoptosis induction and cell cycle progression by flow cytometry, DNA damage by comet assay. Adhesion and transwell migration assays were also performed. RESULTS: Our results showed enhancement of the 5-FU citotoxicity by Olaparib in MMR-deficient HCT116 colon cancer cells. Moreover, the combined treatment with Olaparib and 5-FU induced G2/M arrest, apoptosis and polyploidy in these cells. In MMR proficient HT29 cells, the Olaparib alone reduced clonogenic survival, induced DNA damage accumulation and decreased the adhesion and migration capacities. CONCLUSION: Our results suggest benefits of Olaparib inclusion in CRC treatment, as combination with 5-FU for MMR deficient CRC and as monotherapy for MMR proficient CRC. Thus, combined therapy with Olaparib could be a strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.
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Antineoplásicos/farmacología , Reparación de la Incompatibilidad de ADN/efectos de los fármacos , Fluorouracilo/farmacología , Ftalazinas/farmacología , Piperazinas/farmacología , Apoptosis/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/genética , Daño del ADN , Reparación del ADN/efectos de los fármacos , Sinergismo Farmacológico , Células HCT116 , HumanosRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable and devastating malignant tumors. Epigenetic modifications such as DNA methylation and histone modification regulate tumor initiation and progression. However, the contribution of histone variants in PDAC is unknown. Here, we demonstrated that the histone variant H2A.Z is highly expressed in PDAC cell lines and PDAC patients and that its overexpression correlates with poor prognosis. Moreover, all three H2A.Z isoforms (H2A.Z.1, H2A.Z.2.1, and H2A.Z.2.2) are highly expressed in PDAC cell lines and PDAC patients. Knockdown of these H2A.Z isoforms in PDAC cell lines induces a senescent phenotype, cell cycle arrest in phase G2/M, increased expression of cyclin-dependent kinase inhibitor CDKN2A/p16, SA-ß-galactosidase activity and interleukin 8 production. Transcriptome analysis of H2A.Z-depleted PDAC cells showed altered gene expression in fatty acid biosynthesis pathways and those that regulate cell cycle and DNA damage repair. Importantly, depletion of H2A.Z isoforms reduces the tumor size in a mouse xenograft model in vivo and sensitizes PDAC cells to gemcitabine. Overexpression of H2A.Z.1 and H2A.Z.2.1 more than H2A.Z.2.2 partially restores the oncogenic phenotype. Therefore, our data suggest that overexpression of H2A.Z isoforms enables cells to overcome the oncoprotective barrier associated with senescence, favoring PDAC tumor grow and chemoresistance. These results make H2A.Z a potential candidate as a diagnostic biomarker and therapeutic target for PDAC.
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Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , beta-Galactosidasa/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Envejecimiento/genética , Animales , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Transformación Celular Neoplásica/genética , Daño del ADN/efectos de los fármacos , Metilación de ADN/genética , Reparación del ADN/efectos de los fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Resistencia a Antineoplásicos/genética , Epigénesis Genética/genética , Xenoinjertos , Histonas/genética , Humanos , Ratones , GemcitabinaRESUMEN
BACKGROUND: Omeprazole (OME), a most frequently used proton pump inhibitor in gastric acidosis, is evident to show many adverse effects, including genetic instability. This study evaluated toxicogenic effects of OME in Mus musculus. METHODS: For this study, 40 male Swiss mice were divided into 8 groups (n = 5) and treated with OME at doses of 10, 20, and 40 mg/kg and/or treated with the antioxidants retinol palmitate (100 IU/kg) and ascorbic acid (2.0 µM/kg). Cyclophosphamide 50 mg/kg, (cytotoxic agent) and the vehicle were served as positive and negative control group, respectively. After 14 days of treatment, the stomach cells along with the bone marrow and peripheral blood lymphocytes were collected and submitted to the comet assay (alkaline version) and micronucleus test. Additionally, hematological and biochemical parameters of the animals were also determined inspect of vehicle group. RESULTS: The results suggest that OME at all doses induced genotoxicity and mutagenicity in the treated cells. However, in association with the antioxidants, these effects were modulated and/or inhibited along with a DNA repair capacity. CONCLUSIONS: Taken together, antioxidants (such as retinol palmitate and ascorbic acid) may be one of the best options to counteract OME-induced cytogenetic instability.
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Antioxidantes/farmacología , Ácido Ascórbico/farmacología , Diterpenos/farmacología , Omeprazol/toxicidad , Ésteres de Retinilo/farmacología , Animales , Antineoplásicos/farmacología , Ensayo Cometa , Ciclofosfamida/toxicidad , Reparación del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Mutagénesis/efectos de los fármacos , Omeprazol/administración & dosificación , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/toxicidadRESUMEN
INTRODUCTION: One of the most used regimens to treat breast cancer is the dose-dense ACT protocol, a combination of anthracycline doxorubicin (DOX) with cyclophosphamide and paclitaxel (PCTX). However, many tumors show resistance to the protocols applied. It is known that the nucleotide excision repair (NER) pathway acts by removing the DOX-generated lesions, and this, together with other DNA repair pathways, can modulate the response to treatment. AIMS: To evaluate the in vitro growth profile of breast cancer cells (MCF7), and the modulation of DNA repair genes, submitted to a protocol using DOX and PCTX in a similar regimen to what is used in clinical practice. MAIN METHODS: MCF7 cells were treated with repeated cycles of DOX and PCTX and followed-up during and after each of the treatments. The population doubling of the remaining cells was calculated during the complete protocol and DNA repair gene expression was evaluated at different time-points. KEY FINDINGS: An increase in all NER genes analyzed after the DOX treatment was observed, but not after the PCTX treatment. MRE11was overexpressed at all evaluated time-points. There was a resumption of NER genes overexpression profile when cells were maintained for follow-up and retook their growth pattern, indicating that DNA repair pathways can modulate their expression during the chemotherapy exposure.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Reparación del ADN/efectos de los fármacos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Paclitaxel/administración & dosificaciónRESUMEN
Cancer genome instability arises from diverse defects in DNA-repair machinery, which make cancer cells more susceptible to DNA targeting agents. The interrelation between DNA repair deficiency and the increased effect of DNA targeting agents highlights the double-strand break (DSB) repair, which comprises the homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. The DNA targeting agents are classified into two major groups: non-covalent DNA binding agents and covalent DNA-reactive agents. Although these agents have well-known limitations, such as resistance and secondary carcinogenesis risk, they are extremely important in today's real-life cancer therapy in combination with targeted therapy and immunotherapy. Indeed, DNA targeting drugs are promising therapeutics with a precise application through the background of cancer-specific DNA repair failure. In the current review, the mechanisms of action of diversified DNA-targeting agents, as well as the modulation of DNA repair pathways to increase the DNA-damaging drugs efficacy are presented. Finally, DNA-targeting-based therapies are discussed considering risks, resistance and its uses in the medicine precision era.
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Antineoplásicos/uso terapéutico , Carcinogénesis , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Humanos , Medicina de Precisión , Factores de RiesgoRESUMEN
Considering the importance and lack of data of toxicogenomic approaches on occupational exposure to anesthetics, we evaluated possible associations between waste anesthetic gases (WAGs) exposure and biological effects including oxidative stress, DNA damage, inflammation, and transcriptional modulation. The exposed group was constituted by anesthesia providers who were mainly exposed to the anesthetics sevoflurane and isoflurane (10 ppm) and to a lesser degree to nitrous oxide (150 ppm), and the control group was constituted by physicians who had no exposure to WAGs. The oxidative stress markers included oxidized DNA bases (comet assay), malondialdehyde (high-performance liquid chromatography [HPLC]), nitric oxide metabolites (ozone-chemiluminescence), and antioxidative markers, including individual antioxidants (HPLC) and antioxidant defense marker (ferric reducing antioxidant power by spectrophotometry). The inflammatory markers included high-sensitivity C-reactive protein (chemiluminescent immunoassay) and the proinflammatory interleukins IL-6, IL-8 and IL-17A (flow cytometry). Telomere length and gene expression related to DNA repair (hOGG1 and XRCC1), antioxidant defense (NRF2) and inflammation (IL6, IL8 and IL17A) were evaluated by real-time quantitative polymerase chain reaction. No significant differences (p > .0025) between the groups were observed for any parameter evaluated. Thus, under the conditions of the study, the findings suggest that occupational exposure to WAGs is not associated with oxidative stress or inflammation when evaluated in serum/plasma, with DNA damage evaluated in lymphocytes and leucocytes or with molecular modulation assessed in peripheral blood cells in university anesthesia providers. However, it is prudent to reduce WAGs exposure and to increase biomonitoring of all occupationally exposed professionals.
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Anestesia/efectos adversos , Anestésicos por Inhalación/efectos adversos , Daño del ADN/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Inflamación/inducido químicamente , Exposición Profesional/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Adulto , Anciano , Contaminantes Ocupacionales del Aire/efectos adversos , Antioxidantes/metabolismo , Reparación del ADN/efectos de los fármacos , Femenino , Hospitales , Humanos , Inflamación/metabolismo , Isoflurano/efectos adversos , Masculino , Persona de Mediana Edad , Óxido Nitroso/efectos adversos , Sevoflurano/efectos adversosRESUMEN
Flavonoids are a diverse family of plant compounds that are involved in pigmentation, protection, and endogenous regulation. Flavonoids also have medicinal applications, suggesting that they may exert chemoprotective effects. However, some studies have shown, that some plant flavonoids have oxidative and toxic effects, including those produced by Schinus terebinthifolius. In Brazil, extracts of this plant are widely used for medical purposes. In this study, we analyzed the mutagenic potential of two flavonoid-enriched fractions from Brazilian pepper tree stem bark using Escherichia coli CC strains deficient and proficient in enzymes involved in the DNA repair of oxidative lesions. The highest mutagenic response was detected in the CC104mutMmutY strain but CC104mutY showed a higher mutation frequency than CC104mutM. The spectrum of mutations induced in plasmid DNA is composed of mutations typically caused by oxidative lesions. However, a new type of lesion must be occurred to explain the cytotoxicity, higher mutation rates in the CC104mutY strain, and the rare A:T â T:A and G:C â C:G transversions found in this work.
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Anacardiaceae/efectos adversos , Flavonoides/efectos adversos , Mutación/efectos de los fármacos , Corteza de la Planta/efectos adversos , Extractos Vegetales/efectos adversos , Árboles/efectos adversos , Secuencia de Bases , Brasil , Reparación del ADN/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Mutágenos/efectos adversosRESUMEN
Poly(ADP-ribosyl)polymerase (PARP) synthesizes poly(ADP-ribose) (PAR), which is anchored to proteins. PAR facilitates multiprotein complexes' assembly. Nuclear PAR affects chromatin's structure and functions, including transcriptional regulation. In response to stress, particularly genotoxic stress, PARP activation facilitates DNA damage repair. The PARP inhibitor Olaparib (OLA) displays synthetic lethality with mutated homologous recombination proteins (BRCA-1/2), base excision repair proteins (XRCC1, Polß), and canonical nonhomologous end joining (LigIV). However, the limits of synthetic lethality are not clear. On one hand, it is unknown whether any limiting factor of homologous recombination can be a synthetic PARP lethality partner. On the other hand, some BRCA-mutated patients are not responsive to OLA for still unknown reasons. In an effort to help delineate the boundaries of synthetic lethality, we have induced DNA damage in VERO cells with the radiomimetic chemotherapeutic agent bleomycin (BLEO). A VERO subpopulation was resistant to BLEO, BLEO + OLA, and BLEO + OLA + ATM inhibitor KU55933 + DNA-PK inhibitor KU-0060648 + LigIV inhibitor SCR7 pyrazine. Regarding the mechanism(s) behind the resistance and lack of synthetic lethality, some hypotheses have been discarded and alternative hypotheses are suggested.
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Bleomicina/farmacología , Cromonas/farmacología , Morfolinas/farmacología , Ftalazinas/farmacología , Piperazinas/farmacología , Pirimidinas/farmacología , Pironas/farmacología , Bases de Schiff/farmacología , Tiofenos/farmacología , Animales , Antineoplásicos/farmacología , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Chlorocebus aethiops , ADN Ligasa (ATP)/antagonistas & inhibidores , Reparación del ADN/efectos de los fármacos , Proteína Quinasa Activada por ADN/antagonistas & inhibidores , Combinación de Medicamentos , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Células VeroRESUMEN
Cadmium (Cd) is a toxic metal occurring in the environment naturally. Almond mushroom (Agaricus brasiliensis) is a well-known cultivated edible and medicinal mushroom. In the past few decades, Cd accumulation in A.brasiliensis has received increasing attention. However, the molecular mechanisms of Cd-accumulation in A. brasiliensis are still unclear. In this paper, a comparative transcriptome of two A.brasiliensis strains with contrasting Cd accumulation and tolerance was performed to identify Cd-responsive genes possibly responsible for low Cd-accumulation and high Cd-tolerance. Using low Cd-accumulating and Cd-tolerant (J77) and high Cd-accumulating and Cd-sensitive (J1) A.brasiliensis strains, we investigated 0, 2 and 5 mg L-1 Cd-effects on mycelium growth, Cd-accumulation and transcriptome revealed by RNA-Seq. A total of 57,884 unigenes were obtained. Far less Cd-responsive genes were identified in J77 mycelia than those in J1 mycelia (e.g., ABC transporters, ZIP Zn transporter, Glutathione S-transferase and Cation efflux (CE) family). The higher Cd-accumulation in J1 mycelia might be due to Cd-induced upregulation of ZIP Zn transporter. Cd impaired cell wall, cell cycle, DNA replication and repair, thus decreasing J1 mycelium growth. Cd-stimulated production of sulfur-containing compounds, polysaccharides, organic acids, trehalose, ATP and NADPH, and sequestration of Cd might be adaptive responses of J1 mycelia to the increased Cd-accumulation. DNA replication and repair had better stability under 2 mg L-1 Cd, but greater positive modifications under 5 mg L-1 Cd. Better stability of DNA replication and repair, better cell wall and cell cycle stability might account for the higher Cd-tolerance of J77 mycelia. Our findings provide a comprehensive set of DEGs influenced by Cd stress; and shed light on molecular mechanism of A.brasiliensis Cd accumulation and Cd tolerance.
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Agaricus/metabolismo , Cadmio/metabolismo , Transcriptoma , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Agaricus/efectos de los fármacos , Agaricus/genética , Cadmio/toxicidad , Reparación del ADN/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Tolerancia a Medicamentos , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Perfilación de la Expresión Génica , Regulación Fúngica de la Expresión Génica , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Micelio/química , Micelio/efectos de los fármacos , Micelio/crecimiento & desarrollo , Polisacáridos/metabolismo , ARN de Hongos/química , ARN de Hongos/metabolismo , RNA-SeqRESUMEN
Disruption of the tumor suppressor PTEN, either at the protein or genomic level, plays an important role in human cancer development. The high frequency of PTEN deficiency reported across several cancer subtypes positions therapeutic approaches that exploit PTEN loss-of-function with the ability to significantly impact the treatment strategies of a large patient population. Here, we report that an endophytic fungus isolated from a medicinal plant produces an inhibitor of DNA double-strand-break repair. Furthermore, the novel alkaloid product, which we have named irrepairzepine (1), demonstrated synthetic lethal targeting in PTEN-deficient glioblastoma cells. Our results uncover a new therapeutic lead for PTEN-deficient cancers and an important molecular tool toward enhancing the efficacy of current cancer treatments.
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Neoplasias Encefálicas/tratamiento farmacológico , Reparación del ADN/efectos de los fármacos , Endófitos/química , Glioblastoma/tratamiento farmacológico , Fosfohidrolasa PTEN/genética , Mutaciones Letales Sintéticas/genética , Neoplasias Encefálicas/genética , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Ensayo Cometa , Roturas del ADN de Doble Cadena/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ecuador , Glioblastoma/genética , Humanos , Estructura Molecular , Mutágenos/toxicidad , Ensayo de Tumor de Célula MadreRESUMEN
Xanthones are a class of heterocyclic natural products that have been widely studied for their pharmacological potential. In fact, they have been serving as scaffolds for the design of derivatives focusing on drug development. One of the main study targets of xanthones is their anticancer activity. Several compounds belonging to this class have already demonstrated cytotoxic and antitumor effects, making it a promising group for further exploration. This review therefore focuses on recently published studies, emphasizing their natural and synthetic sources and describing the main mechanisms of action responsible for the anticancer effect of promising xanthones.
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Productos Biológicos/química , Xantonas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Productos Biológicos/metabolismo , Productos Biológicos/uso terapéutico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Plantas/química , Plantas/metabolismo , Xantonas/metabolismo , Xantonas/uso terapéuticoRESUMEN
Lung cancer patients face a dismal prognosis mainly due to the low efficacy of current available treatments. Cisplatin is the first-line chemotherapy treatment for those patients, however, resistance to this drug is a common and yet not fully understood phenomenon. Aiming to shed new light into this puzzle, we used established normal and malignant lung cell lines displaying different sensitivity towards cisplatin treatment. We observed a negative correlation between cell viability and DNA damage induction upon cisplatin treatment. Interestingly, drug sensitivity in those cell lines was not due to either difference on DNA repair capacity, or in the amount of membrane ion channel commonly used for cisplatin uptake. Also, we noted that glutathione intracellular levels, and expression and activity of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) were determinant for cisplatin cytotoxicity. Remarkably, analysis of gene expression in non-small cell lung cancer patients of the TCGA data bank revealed that there is a significant lower overall survival rate in the subset of patients bearing tumors with unbalanced levels of NRF2/KEAP1 and, as consequence, increased expression of NRF2 target genes. Thus, the results indicate that NRF2 and glutathione levels figure as important cisplatin resistance biomarkers in lung cancer.
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Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Reparación del ADN , Glutatión/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal , Células A549/efectos de los fármacos , Células A549/metabolismo , Antioxidantes/metabolismo , Biomarcadores de Tumor/metabolismo , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Reparación del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Citometría de Flujo , Humanos , Neoplasias Pulmonares/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/efectos de los fármacosRESUMEN
Glyphosate is a broad-spectrum herbicide that is used worldwide. It represents a potential harm to surface water, and when commercially mixed with surfactants, its uptake is greatly magnified. The most well-known glyphosate-based product is Roundup. This herbicide is potentially an endocrine disruptor and many studies have shown the cytotoxicity potential of glyphosate-based herbicides. In breast cancer (BC) cell lines it has been demonstrated that glyphosate can induce cellular proliferation via estrogen receptors. Therefore, we aimed to identify gene expression changes in ER+ and ER- BC cell lines treated with Roundup and AMPA, to address changes in canonical pathways that would be related or not with the ER pathway, which we believe could interfere with cell proliferation. Using the Human Transcriptome Arrays 2.0, we identified gene expression changes in MCF-7 and MDA-MB-468 exposed to low concentrations and short exposure time to Roundup Original and AMPA. The results showed that at low concentration (0.05% Roundup) and short exposure (48h), both cell lines suffered deregulation of 11 canonical pathways, the most important being cell cycle and DNA damage repair pathways. Enrichment analysis showed similar results, except that MDA-MB-468 altered mainly metabolic processes. In contrast, 48h 10mM AMPA showed fewer differentially expressed genes, but also mainly related with metabolic processes. Our findings suggest that Roundup affects survival due to cell cycle deregulation and metabolism changes that may alter mitochondrial oxygen consumption, increase ROS levels, induce hypoxia, damage DNA repair, cause mutation accumulation and ultimately cell death. To our knowledge, this is the first study to analyze the effects of Roundup and AMPA on gene expression in triple negative BC cells. Therefore, we conclude that both compounds can cause cellular damage at low doses in a relatively short period of time in these two models, mainly affecting cell cycle and DNA repair.
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Neoplasias de la Mama/genética , Glicina/análogos & derivados , Transducción de Señal/genética , Transcriptoma/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Receptor alfa de Estrógeno/genética , Estrógenos/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glicina/farmacología , Herbicidas/efectos adversos , Herbicidas/farmacología , Humanos , Células MCF-7 , Transducción de Señal/efectos de los fármacos , Transcriptoma/efectos de los fármacos , GlifosatoRESUMEN
Caffeine is a compound that can exert physiological-beneficial effects in the organism. Nevertheless, there are controversies about its protective-antioxidant and/or its negative genotoxic effect. To abound on the analysis of the possible genotoxic/antioxidant effect of caffeine, we used as research model the yeast Yarrowia lipolytica parental strain, and mutant strains (∆rad52 and ∆ku80), which are deficient in the DNA repair mechanisms. Caffeine (5 mM) showed a cytostatic effect on all strains, but after 72 h of incubation the parental and ∆ku80 strains were able to recover of this inhibitory effect on growth, whereas ∆rad52 was unable to recover. When cells were pre-incubated with caffeine and H2O2 or incubated with a mixture of both agents, a higher inhibitory effect on growth of mutant strains was observed and this effect was noticeably greater for the Δrad52 strain. The toxic effect of caffeine appears to be through a mechanism of DNA damage (genotoxic effect) that involves DSB generation since, in all tested conditions, the growth of Δrad52 strain (cells deficient in HR DNA repair mechanism) was more severely affected.