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1.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360791

RESUMO

Rhabdomyosarcoma (RMS) is a malignant soft tissue cancer that develops mostly in children and young adults. With regard to histopathology, four rhabdomyosarcoma types are distinguishable: embryonal, alveolar, pleomorphic and spindle/sclerosing. Currently, increased amounts of evidence indicate that not only gene mutations, but also epigenetic modifications may be involved in the development of RMS. Epigenomic changes regulate the chromatin architecture and affect the interaction between DNA strands, histones and chromatin binding proteins, thus, are able to control gene expression. The main aim of the study was to assess the role of protein arginine methyltransferases (PRMT) in the cellular biology of rhabdomyosarcoma. In the study we used two pan-inhibitors of PRMT, called AMI-1 and SAH, and evaluated their effects on proliferation and apoptosis of RMS cells. We observed that AMI-1 and SAH reduce the invasive phenotype of rhabdomyosarcoma cells by decreasing their proliferation rate, cell viability and ability to form cell colonies. In addition, microarray analysis revealed that these inhibitors attenuate the activity of the PI3K-Akt signaling pathway and affect expression of genes related to it.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Naftalenossulfonatos/farmacologia , Proteína-Arginina N-Metiltransferases , Rabdomiossarcoma , Transdução de Sinais/efeitos dos fármacos , Ureia/análogos & derivados , Linhagem Celular Tumoral , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/enzimologia , Rabdomiossarcoma/patologia , Ureia/farmacologia
2.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200927

RESUMO

Bacterial cellulose membranes (BCs) are becoming useful as a drug delivery system to the skin. However, there are very few reports on their application of plant substances to the skin. Komagataeibacter xylinus was used for the production of bacterial cellulose (BC). The BC containing 5% and 10% ethanolic extract of Epilobium angustifolium (FEE) (BC-5%FEE and BC-10%FEE, respectively) were prepared. Their mechanical, structural, and antioxidant properties, as well as phenolic acid content, were evaluated. The bioavailability of BC-FESs using mouse L929 fibroblasts as model cells was tested. Moreover, In Vitro penetration through the pigskin of the selected phenolic acids contained in FEE and their accumulation in the skin after topical application of BC-FEEs was examined. The BC-FEEs were characterized by antioxidant activity. The BC-5% FEE showed relatively low toxicity to healthy mouse fibroblasts. Gallic acid (GA), chlorogenic acid (ChA), 3,4-dihydroxybenzoic acid (3,4-DHB), 4-hydroxybenzoic acid (4-HB), 3-hydroxybenzoic acid (3-HB), and caffeic acid (CA) found in FEE were also identified in the membranes. After topical application of the membranes to the pigskin penetration of some phenolic acid and other antioxidants through the skin as well as their accumulation in the skin was observed. The bacterial cellulose membrane loaded by plant extract may be an interesting solution for topical antioxidant delivery to the skin.


Assuntos
Antioxidantes/administração & dosagem , Celulose/química , Epilobium/química , Fibroblastos/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Pele/efeitos dos fármacos , Administração Tópica , Animais , Bactérias/química , Fibroblastos/metabolismo , Camundongos , Pele/metabolismo , Suínos
3.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33671106

RESUMO

Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics drive the search for new more effective and selective compounds. For this purpose structural modifications of the previously characterized pyridine aalog (S1) were incorporated aiming to obtain an antimitotic inhibitor of satisfactory and specific anticancer activity. Structure-activity relationship analysis of the compounds against a panel of cancer cell lines allowed to select a compound with a thiophene ring at C5 of a 3,4-dihydropyridine-2(1H)-thione (S22) with promising antiproliferative activity (IC50 equal 1.71 ± 0.58 µM) and selectivity (SI = 21.09) against melanoma A375 cells. Moreover, all three of the most active compounds from the antiproliferative study, namely S1, S19 and S22 showed better selectivity against A375 cells than reference drug, suggesting their possible lower toxicity and wider therapeutic index. As further study revealed, selected compounds inhibited tubulin polymerization via colchicine binding site in dose dependent manner, leading to aberrant mitotic spindle formation, cell cycle arrest and apoptosis. Summarizing, the current study showed that among obtained mitotic-specific inhibitors analogue with thiophene ring showed the highest antiproliferative activity and selectivity against cancer cells.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Di-Hidropiridinas/química , Melanoma/tratamento farmacológico , Tionas/química , Apoptose , Desenho de Fármacos , Humanos , Melanoma/patologia , Mitose , Estrutura Molecular , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Células Tumorais Cultivadas
4.
Bioorg Chem ; 88: 102930, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31039469

RESUMO

The key function of microtubules and mitotic spindle in cell division make them attractive targets in anticancer therapy. In the present study, functionalized in 3 position 2-phenyl- and 2-alkylbenzo[b]furans were synthesized and evaluated as antitumor agents. Among the synthesized derivatives 13a, 13b and 14 exhibited the most potent antiproliferative activity against human melanoma A375 cell line with IC50 values of 2.85 µM, 0.86 µM, 0.09 µM, respectively. The most promising compound defined was 14 with three methoxy groups in the 3-aroyl substituent and 7-methoxy group in 2-phenylbenzo[b]furan skeleton. Tubulin polymerization assay, confocal microscopy imaging and flow cytometry analysis revealed that 2-phenyl-3-aroylbenzo[b]furans (13a, 13b and 14) inhibited tubulin polymerization leading to disruption of mitotic spindle formation, cell cycle arrest in G2/M phase and apoptosis.


Assuntos
Antineoplásicos/farmacologia , Furanos/farmacologia , Melanoma/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/química , Humanos , Melanoma/patologia , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
5.
Future Med Chem ; 10(20): 2395-2410, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30325216

RESUMO

AIM: The mitotic spindle plays a key role in cell division which makes it an important target in cancer therapy. In the present study the antiproliferative activity of 4-benzyl-5-phenyl-3,4-dihydropyrimidine-2(1H)-thione (1) and its pyridine bioisoster (2) were evaluated and compared with monastrol (MON), the first known cell-permeable small molecule which disrupts bipolar spindle formation by inhibiting Eg5-kinesin activity. RESULTS: Our data revealed that compound 2 showed higher antiproliferative activity than MON against MCF7 and A375 cell lines and comparable reversible cell cycle inhibition in G2/M phase. However, compound 2 produced distinct phenotype from monoastral spindles, and did not affect Eg5 ATPase activity. CONCLUSION: The activity of compound 2 may suggest its new promising anticancer mechanism (different than MON), targeting other component required for spindle bipolarity.


Assuntos
Di-Hidropiridinas/farmacologia , Pirimidinas/farmacologia , Fuso Acromático/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Desenho de Fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Cinesina/metabolismo , Pontos de Checagem da Fase M do Ciclo Celular , Microscopia Confocal , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/metabolismo , Fuso Acromático/metabolismo , Tionas/metabolismo , Tubulina (Proteína)/metabolismo
6.
Toxicol In Vitro ; 41: 205-213, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28323107

RESUMO

In recent years, graphene and its derivatives have been extensively investigated because of their unique properties, which can be used in many fields including biomedical applications. Therefore, detailed biological study is required. In the current paper the detailed toxicological studies on single and four layer graphene oxide (GO) nanoflakes is presented. The morphology and size of the nanomaterials were characterized via atomic force microscopy. Cytotoxicity, proliferation and internalization study were performed using various methods, including optical, confocal and Raman microscopy imaging, flow cytometry analysis, colorimetric and luminescent cell assays. Our first findings undeniably show that the nanomaterials' functionalization has a considerable impact on their behavior in a biological environment. The cytotoxicity assay confirmed comparable, dose dependent cytotoxicity of single and four layers GO flakes. The differences between these two nanomaterials became more distinct during cell proliferation study and ROS detection. Namely, markedly stronger inhibition of cell proliferation and higher ROS generation by one-layer GO-PEG than four-layer GO-PEG were observed. Cell imaging revealed efficient internalization of the both GO nanoflakes in a time dependent manner. These findings emphasize the role of number of layer and functionalization in GO toxicological characteristics and may provide helpful information for their further biomedical applications.


Assuntos
Grafite/toxicidade , Nanoestruturas/toxicidade , Óxidos/toxicidade , Polietilenoglicóis/toxicidade , Apoptose/efeitos dos fármacos , Transporte Biológico , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Grafite/química , Humanos , Células MCF-7 , Nanoestruturas/química , Necrose/induzido quimicamente , Óxidos/química , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/metabolismo
7.
Org Biomol Chem ; 12(21): 3427-40, 2014 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-24752551

RESUMO

An easy and novel approach to synthesize 4,5-diaryl functionalized 3,4-dihydropyrimidine-2(1H)-thiones via addition of aryllithiums to 5-aryl substituted pyrimidine-2(1H)-thiones, which could be regarded as a method complementary to the most widely used Biginelli-type synthesis, is described. In the reaction of aryllithiums with N-(Me)Bn substituted pyrimidine-2(1H)-thiones a high degree of regioselectivity of addition, leading to 4-aryl adducts, was achieved. Selected compounds tested for their in vitro anticancer activity against four human cancer cell lines showed the greatest activity against breast cancer (MCF7). 1-Benzyl-4-(3-hydroxyphenyl)-5-phenyl substituted 3,4-dihydropyrimidine-2(1H)-thione (10g) exhibiting 10-fold more potent activity than the best known monastrol (MON) stands as a promising candidate for further scaffold and asymmetric synthesis.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Tionas/síntese química , Tionas/farmacologia , Antineoplásicos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Espectroscopia de Prótons por Ressonância Magnética , Pirimidinas/química , Pirimidinas/farmacologia , Estereoisomerismo , Tionas/química
8.
Biomed Microdevices ; 16(3): 449-58, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24676537

RESUMO

In this paper, we study synthesis and characteristics of mesoporous silica nanotubes modified by titanium dioxide, as well as their antimicrobial properties and influence on mitochondrial activity of mouse fibroblast L929. Nanocrystalized titania is confined in mesopores of silica nanotubes and its light activated antibacterial response is revealed. The analysis of the antibacterial effect on Escherichia coli. (ATCC 25922) shows strong enhancement during irradiation with the artificial visible and ultraviolet light in respect to the commercial catalyst and control sample free from the nanomaterials. In darkness, the mesoporous silica/titania nanostructures exhibited antibacterial activity dependent on the stirring speed of the suspension containing nanomaterials. Obtained micrograph proved internalization of the sample into the microorganism trough the cell membrane. The analysis of the mitochondrial activity and amount of lactate dehydrogenase released from mouse fibroblast cells L929 in the presence of the sample were determined with LDH and WST1 assays, respectively. The synthesized silica/titania antibacterial agent also exhibits pronounced photoinduced inactivation of the bacterial growth under the artificial visible and UV light irritation in respect to the commercial catalyst. Additionally, mesoporous silica/titania nanotubes were characterized in details by means of high resolution transmission electron microscopy (HR-TEM), XRD and BET Isotherm.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Nanopartículas/química , Nanotubos/química , Dióxido de Silício/química , Titânio/química , Titânio/farmacologia , Animais , Antibacterianos/toxicidade , Linhagem Celular , Escherichia coli/efeitos dos fármacos , Camundongos , Processos Fotoquímicos , Porosidade , Titânio/toxicidade
9.
Pharmacogenomics ; 15(2): 179-88, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24444408

RESUMO

BACKGROUND: Tacrolimus (TAC), acting as a calcineurin inhibitor, is an immunosuppressant widely used after kidney transplantation. TAC requires blood concentration monitoring due to large interindividual variability in its pharmacokinetics and a narrow therapeutic index. Since genetic factors are considered responsible for a part of the observed pharmacokinetic variability, hereby SNPs within the CYP3A4, CYP3A5 and ABCB1 genes in kidney transplant patients of Polish Caucasian origin were investigated. PATIENTS & METHODS: A total of 241 patients treated with TAC through the first year after kidney transplantation were genotyped for the presence of common SNPs: rs776746:A>G (CYP3A5*3), rs35599367:C>T (CYP3A4*22), rs2740574:A>G (CYP3A4*1B) and rs1045642:C>T (ABCB1 3435C>T) using TaqMan(®) assays. RESULTS: CYP3A5 expressers received significantly higher weight-adjusted TAC doses, and were characterized by markedly lower C0 and dose adjusted C0 values in the course of treatment. CYP3A4*1B was significantly associated with TAC pharmacokinetics in univariate analysis. Impact of the CYP3A4*22 allele was significant only at particular time points, that is, 3 months after transplantation, with marginal significance 6 months after transplantation. The ABCB1 genotype did not influence TAC pharmacokinetics. Multivariate analysis of all the studied loci demonstrated that only the CYP3A5*1 (starting from month 1) and CYP3A4*22 alleles (at 3 and 6 months) were independent predictors of TAC dose-adjusted C0. CONCLUSION: Our results confirm the impact of the CYP3A4*22 allele on TAC pharmacokinetics, as a second significant genetic factor (in addition to the CYP3A5*1 allele) influencing TAC dose-adjusted blood concentrations in kidney transplant recipients.


Assuntos
Citocromo P-450 CYP3A/administração & dosagem , Tacrolimo/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/administração & dosagem , Humanos , Imunossupressão/métodos , Transplante de Rim/efeitos adversos , Polimorfismo de Nucleotídeo Único
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