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1.
Life Sci ; 285: 119949, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34543640

RESUMO

AIMS: Swietenia macrophylla have been considered for the treatment of various diseases, including anticancer activity. This study aimed to investigate the anticancer activity of S. macrophylla leaves extract and its isolated compound towards human colorectal cancer cell line. MAIN METHODS: Hexanic extract of S. macrophylla leaves demonstrated relevant cytotoxicity only against colon cancer cell line HCT116. KEY FINDINGS: Our results showed significant DNA damage and apoptosis after treatment with the hexanic extract of S. macrophylla. Moreover, no toxicity was noticed for the animal model. The isolated compound limonoid L1 showed potent cytotoxicity against cancer cell lines with IC50 at 55.87 µg mL-1. Limonoid L1 did not trigger any cell membrane rupture in the mice erythrocytes suggesting no toxicity. The antiproliferative effect of L1 was confirmed in colorectal cancer cells by clonogenic assay, inducing G2/M arrest, apoptosis, and DNA damage in cancer-type cells. SIGNIFICANCE: L1 reduced BCL2 and increased ATM, CHK2, TP53, ARF, CDK1, CDKN1A, and CASP3 in the colorectal cancer cell line. These findings suggest that limonoid L1 isolated from S. macrophylla can be a promising anticancer agent in managing colorectal cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Colorretais/patologia , Dano ao DNA , Limoninas/farmacologia , Meliaceae/química , Animais , Neoplasias Colorretais/metabolismo , Eritrócitos/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HCT116 , Hemólise , Humanos , Limoninas/isolamento & purificação , Limoninas/uso terapêutico , Camundongos , Extratos Vegetais/química , Extratos Vegetais/farmacologia
2.
J Cell Biochem ; 122(10): 1376-1388, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34160883

RESUMO

Gastric cancer is one of the most common and deadly types of cancer in the world, and poor prognosis with treatment failure is widely reported in the literature. In this context, kinases have been considered a relevant choice for targeted therapy in gastric cancer. Here, we explore the antiproliferative and antimigratory effects of the AURKA inhibitor and the prognostic and therapeutic value as a biomarker of gastric cancer. A total of 145 kinase inhibitors were screened to evaluate the cytotoxic or cytostatic effects in the gastric cancer cell line. Using the Alamar Blue assay, flow cytometry, quantitative polymerase chain reaction, and observation of caspase 3/7 activity and cell migration, we investigated the antiproliferative, proapoptotic, and antimigratory effects of the AURKA inhibitor. Moreover, AURKA overexpression was evaluated in the gastric cell lines and the gastric tumor tissue. Out of the 145 inhibitors, two presented the highest antiproliferative effect. Both molecules can induce apoptosis by the caspases 3/7 pathway in addition to inhibiting cancer cell migration, mainly the AURKA inhibitor. Moreover, molecular docking analysis revealed that GW779439X interacts in the active site of the AURKA enzyme with similar energy as a well-described inhibitor. Our study identified AURKA overexpression in the gastric cancer cell line and gastric tumor tissue, revealing that its overexpression in patients with cancer is correlated with low survival. Therefore, it is feasible to suggest AURKA as a potential marker of gastric cancer, besides providing robust information for diagnosis and estimated survival of patients. AURKA can be considered a new molecular target used in the prognosis and therapy of gastric cancer.

3.
Int J Biol Macromol ; 179: 1-19, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667553

RESUMO

Three coronaviruses (CoVs) have threatened the world population by causing outbreaks in the last two decades. In late 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged and caused the coronaviruses to disease 2019 (COVID-19), leading to the ongoing global outbreak. The other pandemic coronaviruses, SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV), share a considerable level of similarities at genomic and protein levels. However, the differences between them lead to distinct behaviors. These differences result from the accumulation of mutations in the sequence and structure of spike (S) glycoprotein, which plays an essential role in coronavirus infection, pathogenicity, transmission, and evolution. In this review, we brought together many studies narrating a sequence of events and highlighting the differences among S proteins from SARS-CoV, MERS-CoV, and SARS-CoV-2. It was performed here, analysis of S protein sequences and structures from the three pandemic coronaviruses pointing out the mutations among them and what they come through. Additionally, we investigated the receptor-binding domain (RBD) from all S proteins explaining the mutation and biological importance of all of them. Finally, we discuss the mutation in the S protein from several new isolates of SARS-CoV-2, reporting their difference and importance. This review brings into detail how the variations in S protein that make SARS-CoV-2 more aggressive than its relatives coronaviruses and other differences between coronaviruses.


Assuntos
COVID-19/virologia , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Animais , COVID-19/epidemiologia , COVID-19/metabolismo , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Glicoproteínas/metabolismo , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Pandemias , Ligação Proteica , Vírus da SARS/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo
4.
SLAS Discov ; 25(7): 801-811, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32458721

RESUMO

High-content screening to monitor disease-modifying phenotypes upon small-molecule addition has become an essential component of many drug and target discovery platforms. One of the most common phenotypic approaches, especially in the field of oncology research, is the assessment of cell viability. However, frequently used viability readouts employing metabolic proxy assays based on homogeneous colorimetric/fluorescent reagents are one-dimensional, provide limited information, and can in many cases yield conflicting or difficult-to-interpret results, leading to misinterpretation of data and wasted resources.The resurgence of high-content, phenotypic screening has significantly improved the quality and breadth of cell viability data, which can be obtained at the very earliest stages of drug and target discovery. Here, we describe a relatively inexpensive, high-throughput, high-content, multiparametric, fluorescent imaging protocol using a live-cell method of three fluorescent probes (Hoechst, Yo-Pro-3, and annexin V), that is amenable to the addition of further fluorophores. The protocol enables the accurate description and profiling of multiple cell death mechanisms, including apoptosis and necrosis, as well as accurate determination of compound IC50, and has been validated on a range of high-content imagers and image analysis software. To validate the protocol, we have used a small library of approximately 200 narrow-spectrum kinase inhibitors and clinically approved drugs. This fully developed, easy-to-use pipeline has subsequently been implemented in several academic screening facilities, yielding fast, flexible, and rich cell viability data for a range of early-stage high-throughput drug and target discovery programs.


Assuntos
Apoptose/genética , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Bibliotecas de Moléculas Pequenas/farmacologia , Colorimetria , Corantes Fluorescentes/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/ultraestrutura , Ensaios de Triagem em Larga Escala , Humanos , Processamento de Imagem Assistida por Computador/métodos , Software
5.
Toxicol In Vitro ; 63: 104735, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31751609

RESUMO

Gastric cancer is the third leading cause of cancer-related death worldwide. To evaluate the anticancer potential and molecular mechanism of biflorin, a prenyl-ortho-naphthoquinone obtained from Capraria biflora L. roots, we used ACP02, a gastric cancer cell line established from a primary diffuse gastric adenocarcinoma. In this study, biflorin was shown to be a potent cytotoxic agent against ACP02 by Alamar Blue and Trypan Blue assays. Morphological analysis indicated cell death with features of necrosis. Furthermore, a decrease in colony formation, migration and invasion of ACP02 cells was observed after treatment with biflorin (1.0, 2.5 and 5.0 µM). Regarding the underlying molecular mechanism of biflorin in ACP02 cells, we observed a decrease in MYC expression and telomere length using FISH. Our findings suggest a novel molecular target of biflorin in ACP02 cells, which may be a significant therapeutic approach for gastric cancer management.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Naftoquinonas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas c-myc/genética , Neoplasias Gástricas/metabolismo
6.
J Ethnopharmacol ; 232: 30-38, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30543916

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Oils and extracts of Eugenia uniflora have been reported as antimicrobial, antifungal, antinociceptive, antiprotozoal, antioxidant and cytotoxic. AIM OF THE STUDY: The oils of five specimens (E1 to E5) that occur in the Brazilian Amazon were extracted, analyzed for their chemical composition, and submitted to antioxidant and cytotoxic assays. MATERIAL AND METHODS: Oils were hydrodistilled, analyzed by GC and GC-MS, and submitted to PCA and HCA analyses. The antioxidant activity of the oils was evaluated by the DPPH radical scavenging and the ß-carotene/linoleic acid assays. Antiproliferative effects of the oils and curzerene were tested against colon (HCT-116), gastric (AGP-01), and melanoma (SKMEL-19) human cancer cell lines and a normal human fibroblast cell line (MRC-5), using MTT assay. RESULTS: Oxygenated sesquiterpenes and sesquiterpene hydrocarbons such as curzerene, selina-1,3,7(11)-trien-2-one, selina-1,3,7(11)-trien-2-one epoxide, germacrene B, caryophyllene oxide, and (E)-caryophyllene were predominant in the oils. PCA and HCA analyses classified the oils samples into four chemotypes. TEAC values of chemotype II (E3 oil, 228.3 ±â€¯19.2 mg TE/mL) and chemotype III (E4 oil, 217.0 ±â€¯23.3 mg TE/mL) displayed significant antioxidant activities. The oils E2 and E4 showed cytotoxic activity against all cell lines tested HCT-116 (IC50 E2:16.26 µg/mL; IC50 E4:9.28 µg/mL), AGP-01, (IC50 E2:12.60 µg/mL; IC50 E4:8.73 µg/mL), SKMEL-19 (IC50 E2:12.20 µg/mL; IC50 E4:15.42 µg/mL), and MRC-5 (IC50 E2:10.27 µg/mL; IC50 E4:14.95 µg/mL). Curzerene showed the more significant activity against melanoma cells (SKMEL-19, IC50:5.17 µM), induced apoptosis at 5.0 µM and 10.0 µM compared to DMSO, exhibiting a decrease in the cell migration at 5.0 µM and 10.0 µM, after 30 h of treatment. CONCLUSION: The curzerene chemotype oil and E. uniflora oils can be indicated as drug candidates for anticancer activity of the lung, colon, stomach, and melanoma, with a real prospect to their subsequent phytotherapeutic development.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Eugenia , Óleos Vegetais/farmacologia , Antineoplásicos/química , Antioxidantes/química , Brasil , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Eugenia/química , Humanos , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Folhas de Planta/química , Óleos Vegetais/química , Cicatrização/efeitos dos fármacos
7.
BMC Cancer ; 18(1): 721, 2018 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-29976158

RESUMO

BACKGROUND: The theory of field effect suggests that the tumor-adjacent area, besides histopathologically normal, undergoes genetic and epigenetic changes that can eventually affect epithelial homeostasis, predisposing the patient to cancer development. One of the many molecular changes described in cancer are microRNAs (miRNAs), which regulates the expression of important genes during carcinogenesis. Thus, the aim of this study was to investigate the field effect in oral cancer. METHODS: We investigated the differential expression profile of four miRNAs (hsa-miR-221, hsa-miR-21, hsa-miR-135b, and hsa-miR-29c) in cancerous oral tissue, in tumor-adjacent tissue and and in non-cancerous tissue samples from healthy volunteers. RESULTS: Our results showed significant overexpression profiles of all four studied miRNAs in cancerous oral tissue compared to non-cancerous samples, as well as in tumor-adjacent tissue compared to cancer-free tissue. No significant difference was found when comparing the expression profile of cancerous and tissue-adjacent tissue groups. We found a negative correlation between the expression of hsa-miR-21 expression and STAT3 in oral squamous cell carcinoma. CONCLUSION: These results suggest that the tissue adjacent to cancer cannot be considered a normal tissue because its molecular aspects are significantly altered. Our data corroborates the hypothesis of field cancerization.


Assuntos
MicroRNAs/análise , Neoplasias Bucais/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/química , Fator de Transcrição STAT3/análise , Transcriptoma
8.
Rev. bras. farmacogn ; 28(3): 333-338, May-June 2018. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-958864

RESUMO

ABSTRACT The organic extracts from stems, roots and leaves of Tephrosia egregia Sandwith, Fabaceae, provided a new flavone, 5-hydroxy-8-(1",2"-epoxy-3"-hydroxy-3"-methylbutyl)-7-methoxyflavone (1), in addition to eleven known compounds: pongaflavone (2), praecansone B (3), 12a-hydroxyrotenone (4), praecansone A, 2',6'-dimethoxy-4',5'-(2",2"-dimethyl)-pyranochalcone, pongachalcone, maackiain, β-sistosterol and its glucoside, p-cumaric acid and cinnamic acid. The structures of all compounds were established on the basis of spectroscopic methods, mainly 1D and 2D NMR and HRESIMS, involving comparison with literature data. Cytotoxicity of compounds 1-4 was evaluated against AGP-01 (cancerous ascitic fluid), HCT-116 (colon adenocarcinoma), HL-60 (leukemia), PC-3 (prostate carcinoma), SF-295 (glioblastoma) and SKMEL 28 (melanoma) cell lines.

10.
Medicines (Basel) ; 4(3)2017 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-28930266

RESUMO

Background:Eugenia species are appreciated for their edible fruits and are known as having anticonvulsant, antimicrobial and insecticidal actions. Methods: The plant material was collected in the southeastern Pará state of Brazil and submitted to hydrodistillation. GC-MS analyzed the oils, and their antioxidant and cytotoxic activities were evaluated by the DPPH and MTT assays. Results: The main components identified in the Eugenia oils were 5-hydroxy-cis-calemene, (2E,6E)-farnesol, (2E,6Z)-farnesol, caryophylla-4(12),8(13)-dien-5α-ol-5ß-ol, E-γ-bisabolene, ß-bisabolene, germacrene D, and ishwarane. The oil of E. egensis showed the most significant antioxidant activity (216.5 ± 11.6 mg TE/mL), followed by the oils of E. flavescens (122.6 ± 6.8 mg TE/mL) and E. patrisii (111.2 ± 12.4 mg TE/mL). Eugenia oils were cytotoxic to HCT-116 (colon cancer) cells by the MTT assay, where the most active was the oil of E. polystachya (10.3 µg/mL), followed by the oils of E. flavescens (13.9 µg/mL) and E. patrisii (16.4 µg/mL). The oils of E. flavescens and E. patrisii showed the highest toxicity for MRC5 (human fibroblast) cells, with values of 14.0 µg/mL and 18.1 µg/mL, respectively. Conclusions: These results suggest that Eugenia oils could be tested in future studies for the treatment of colon cancer and oxidative stress management.

11.
J Environ Public Health ; 2017: 1645074, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28512474

RESUMO

To evaluate the impact of HPV immunization and possible changes in virus type-specific prevalence associated with cervical cancer, it is important to obtain baseline information based on socioeconomic, educational, and environmental characteristics in human populations. We describe these characteristics and the type-specific HPV distribution in 1,183 women diagnosed with cervical cancer in two Brazilian healthcare institutions located at the Southeastern (Rio de Janeiro/RJ) and the Amazonian (Belém/PA) regions. Large differences were observed between women in these regions regarding economic, educational, and reproductive characteristics. The eight most frequent HPV types found in tumor samples were the following: 16, 18, 31, 33, 35, 45, 52, and 58. Some HPV types classified as unknown or low risk were found in tumor samples with single infections, HPV 83 in RJ and HPV 11, 61, and 69 in PA. The proportion of squamous cervical cancer was lower in RJ than in PA (76.3% versus 87.3%, p < 0.001). Adenocarcinoma was more frequent in RJ than in PA (13.5% versus 6.9%, p < 0.001). The frequency of HPV 16 in PA was higher in younger women (p < 0.05). The success of a cervical cancer control program should consider HPV types, local health system organization, and sociodemographic diversity of Brazilian regions.


Assuntos
Papillomaviridae/genética , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/virologia , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Feminino , Genótipo , Humanos , Programas de Imunização/estatística & dados numéricos , Pessoa de Meia-Idade , Infecções por Papillomavirus/epidemiologia , Prevalência , Valores de Referência , Fatores Socioeconômicos , Neoplasias do Colo do Útero/epidemiologia , Adulto Jovem
12.
Artigo em Inglês | MEDLINE | ID: mdl-28265301

RESUMO

BACKGROUND: Histone lysine demethylases (KDMs) are of interest as drug targets due to their regulatory roles in chromatin organization and their tight associations with diseases including cancer and mental disorders. The first KDM inhibitors for KDM1 have entered clinical trials, and efforts are ongoing to develop potent, selective and cell-active 'probe' molecules for this target class. Robust cellular assays to assess the specific engagement of KDM inhibitors in cells as well as their cellular selectivity are a prerequisite for the development of high-quality inhibitors. Here we describe the use of a high-content cellular immunofluorescence assay as a method for demonstrating target engagement in cells. RESULTS: A panel of assays for the Jumonji C subfamily of KDMs was developed to encompass all major branches of the JmjC phylogenetic tree. These assays compare compound activity against wild-type KDM proteins to a catalytically inactive version of the KDM, in which residues involved in the active-site iron coordination are mutated to inactivate the enzyme activity. These mutants are critical for assessing the specific effect of KDM inhibitors and for revealing indirect effects on histone methylation status. The reported assays make use of ectopically expressed demethylases, and we demonstrate their use to profile several recently identified classes of KDM inhibitors and their structurally matched inactive controls. The generated data correlate well with assay results assessing endogenous KDM inhibition and confirm the selectivity observed in biochemical assays with isolated enzymes. We find that both cellular permeability and competition with 2-oxoglutarate affect the translation of biochemical activity to cellular inhibition. CONCLUSIONS: High-content-based immunofluorescence assays have been established for eight KDM members of the 2-oxoglutarate-dependent oxygenases covering all major branches of the JmjC-KDM phylogenetic tree. The usage of both full-length, wild-type and catalytically inactive mutant ectopically expressed protein, as well as structure-matched inactive control compounds, allowed for detection of nonspecific effects causing changes in histone methylation as a result of compound toxicity. The developed assays offer a histone lysine demethylase family-wide tool for assessing KDM inhibitors for cell activity and on-target efficacy. In addition, the presented data may inform further studies to assess the cell-based activity of histone lysine methylation inhibitors.


Assuntos
Inibidores Enzimáticos/metabolismo , Histona Desmetilases/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Biocatálise , Domínio Catalítico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Células HeLa , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histonas/metabolismo , Humanos , Concentração Inibidora 50 , Metilação/efeitos dos fármacos , Microscopia de Fluorescência , Mutagênese , Paclitaxel/toxicidade , Filogenia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estabilidade Proteica/efeitos dos fármacos
13.
Clin Exp Pharmacol Physiol ; 44(6): 613-622, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28271563

RESUMO

The molecular diagnostics revolution has reshaped the practice of oncology by facilitating the identification of genetic, epigenetic and proteomic modifications correlated with cancer, thus delineating 'oncomaps' for various cancer types. These advances have enhanced our understanding of gastric cancer, one of the most fatal diseases worldwide, and culminated in the approval of novel molecular therapies such as trastuzumab. Gastric tumours display recurrent aberrations in key kinase oncogenes such as Her2, epidermal growth factor receptor (EGFR), PI3K, mTOR or c-Met, suggesting that these receptors are amenable to inhibition using specific drug agents. In this review, we examine the mutational landscape of gastric cancer, the use of kinase inhibitors as targeted therapies in gastric tumours and the clinical trials underway for novel inhibitors, highlighting successes, failures and future directions.


Assuntos
Terapia de Alvo Molecular/métodos , Proteínas Quinases/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/enzimologia , Ensaios Clínicos como Assunto , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Gástricas/patologia
14.
Chemosphere ; 175: 130-137, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28211326

RESUMO

Aluminum and its compounds are common contaminants of water and food, as well as medications and cosmetics. The wide distribution of the element facilitates the demand for detailed studies of its biological and toxicological effects. This work aimed to evaluate the possible genotoxic and toxic activity resulting from in vivo and in vitro exposure to Al. For in vivo analysis, 40 Swiss mice were used, various concentrations of hydrated aluminum chloride were administered orally. They were analyzed for possible genic activity and metal cytotoxicity using a micronucleus test (MN), and for toxicity through histopathological evaluation of the extracted organs. For in vitro analysis, lymphocytes from the peripheral blood of 3 healthy donors were used. These cells were exposed to the same chemical agent in various concentrations. In vivo study revealed a significant increase in the number of MN in all Al concentrations. Furthermore, significant alterations in all the organs evaluated were verified by the presence of irreversible lesions (such as necrosis). Corroborating these findings, a significant increase in the quantity of MN in all concentrations with lymphocytes in vitro. In light of this, we suggest that this metal presents genotoxic potential and is potentially a cause of pathological disorders.


Assuntos
Compostos de Alumínio/toxicidade , Cloretos/toxicidade , Dano ao DNA , Linfócitos/efeitos dos fármacos , Adolescente , Cloreto de Alumínio , Compostos de Alumínio/administração & dosagem , Animais , Cloretos/administração & dosagem , Feminino , Humanos , Masculino , Metais/toxicidade , Camundongos , Testes para Micronúcleos , Testes de Mutagenicidade , Adulto Jovem
15.
Lipids Health Dis ; 15(1): 174, 2016 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-27717404

RESUMO

BACKGROUND: Piper aequale Vahl is a small shrub that grows in the shadow of large trees in the Carajás National Forest, Municipality of Parauapebas, Para state, Brazil. The local people have used the plant against rheumatism and inflammation. METHODS: The essential oil of the aerial parts was extracted and analyzed by GC and GC-MS. The MTT colorimetric assay was used to measuring the cytotoxic activity of the oil against human cancer lines. The determination of antioxidant activity of the oil was conducted by DPPH radical scavenging assay. RESULTS: The main constituents were δ-elemene (18.92 %), ß-pinene (15.56 %), α-pinene (12.57 %), cubebol (7.20 %), ß-atlantol (5.87 %), and bicyclogermacrene (5.51 %), totalizing 65.63 % of the oil. The oil displayed a strong in vitro cytotoxic activity against the human cancer cell lines HCT-116 (colon) and ACP03 (gastric) with IC50values of 8.69 µg/ml and 1.54 µg/ml, respectively. The oil has induced the apoptosis in a gastric cancer cells in all tested concentration (0.75-3.0 µg/ml), after 72 h of treatment, when compared to negative control (p < 0.001). Also, the oil showed a significant antioxidant activity (280.9 ± 22.2 mg TE/ml), when analyzed as Trolox equivalent, and a weak acetylcholinesterase inhibition, with a detection limit of 100 ng, when compared to the physostigmine standard (1.0 ng). CONCLUSION: The higher cell growth inhibition induced by the oil of P. aequale is probably due to its primary terpene compounds, which were previously reported in the proliferation inhibition, in stimulation of apoptosis and induction of cell cycle arrest in malignant cells.


Assuntos
Antioxidantes/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Óleos Voláteis/administração & dosagem , Óleos Vegetais/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Antioxidantes/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Células HCT116 , Humanos , Óleos Voláteis/química , Piper/química , Óleos Vegetais/química , Neoplasias Gástricas/patologia
16.
Oncotarget ; 7(28): 43997-44012, 2016 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-27259267

RESUMO

Gastric cancer is one of the most common malignancies and a leading cause of cancer death worldwide. The prognosis of stomach cancer is generally poor as this cancer is not very sensitive to commonly used chemotherapies. Epigenetic modifications play a key role in gastric cancer and contribute to the development and progression of this malignancy. In order to explore new treatment options in this target area we have screened a library of epigenetic inhibitors against gastric cancer cell lines and identified inhibitors for the BET family of bromodomains as potent inhibitors of gastric cancer cell proliferations. Here we show that both the pan-BET inhibitor (+)-JQ1 as well as a newly developed specific isoxazole inhibitor, PNZ5, showed potent inhibition of gastric cancer cell growth. Intriguingly, we found differences in the antiproliferative response between gastric cancer cells tested derived from Brazilian patients as compared to those from Asian patients, the latter being largely resistant to BET inhibition. As BET inhibitors are entering clinical trials these findings provide the first starting point for future therapies targeting gastric cancer.


Assuntos
Azepinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Isoxazóis/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Triazóis/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Azepinas/química , Brasil , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Isoxazóis/química , Estrutura Molecular , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Neoplasias Gástricas/etnologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Triazóis/química
17.
Eur J Med Chem ; 86: 12-6, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-25147145

RESUMO

Benzothiazole hydrazones have been synthesized and evaluated for their in vitro antiproliferative activity against three human cancer cell lines: HL-60 (leukemia), MDAMB-435 (breast) and HCT-8 (colon). The good cytotoxicity for the three cancer cell lines and theoretical profile of compounds 3o and 3p pointed them as promising lead molecules for anticancer drug design.


Assuntos
Antineoplásicos/farmacologia , Benzotiazóis/farmacologia , Hidrazinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzotiazóis/síntese química , Benzotiazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Estrutura Molecular , Relação Estrutura-Atividade
18.
Molecules ; 19(5): 6651-70, 2014 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-24858098

RESUMO

As part of a continuing search for new potential anticancer candidates, we describe the synthesis, cytotoxicity and mechanistic evaluation of a series of 4-oxoquinoline-3-carboxamide derivatives as novel anticancer agents. The inhibitory activity of compounds 10-18 was determined against three cancer cell lines using the MTT colorimetric assay. The screening revealed that derivatives 16b and 17b exhibited significant cytotoxic activity against the gastric cancer cell line but was not active against a normal cell line, in contrast to doxorubicin, a standard chemotherapeutic drug in clinical use. Interestingly, no hemolytical activity was observed when the toxicity of 16b and 17b was tested against blood cells. The in silico and in vitro mechanistic evaluation indicated the potential of 16b as a lead for the development of novel anticancer agents against gastric cancer cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Técnicas de Química Sintética , Simulação por Computador , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Eritrócitos/efeitos dos fármacos , Hemolíticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolonas/química , Neoplasias Gástricas/tratamento farmacológico
19.
Chem Biodivers ; 9(2): 418-27, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22344918

RESUMO

Continuing search for anticancer compounds from the marine environment, we have studied microorganisms that inhabit intertidal sediments of the northeastern Brazilian coast. Of the 32 strains isolated, 13 were selected for biological evaluation of their crude extracts. The acetate extract obtained from a Gram-negative bacterium was strongly active against cancer cell lines with IC(50) values that ranged from 0.04 (HL60 leukemia cells) to 0.26 µg/ml (MDA MB-435 melanoma cells). The bacterium was identified as a Pseudoalteromonas sp. based on 16S rRNA gene sequencing. A bioassay-guided fractionation of the active extract led to the isolation of prodigiosin, a well-known tripyrrole red pigment with immunosuppressive and anticancer activities. Further experiments with ErbB-2 overexpressing cell lines, including HB4a-C3.6 (moderate overexpression), HB4a-C5.2 (high overexpression), and the parental HB4a cell line, were performed. Prodigiosin was moderately active toward HB4a cells with an IC(50) of 4.6 µg/ml, while it was 115 and 18 times more active toward HB4a-C3.6 cells (IC(50) of 0.04 µg/ml) and HB4a-C5.2 (IC(50) of 0.26 µg/ml) cells, respectively. These data suggest that, in spite of its previously described apoptosis-inducing properties, prodigiosin can selectively recognize cells overexpressing ErbB-2, which could be highly appealing in human breast cancer therapy.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Prodigiosina/farmacologia , Pseudoalteromonas/efeitos dos fármacos , Antibacterianos/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Brasil , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Filogenia , Prodigiosina/isolamento & purificação
20.
Eur J Med Chem ; 46(9): 3778-87, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21696865

RESUMO

The antiproliferative effects of twenty-eight tetrasubstituted olefins bearing a ferrocenyl group, including six never-reported compounds, were evaluated against SF-295 (human glioblastoma), HCT-8 (human colon cancer), MDA-MB-435 (human melanoma) and HL-60 (human promyelocytic leukemia) using the MTT test. IC(50) values were determined for twenty-three active compounds and of these, ten compounds had IC(50) values lower than 2 µM on one or more cell lines. Of all the compounds, only two produced significant amounts of ROS on HL-60 cells, and ROS production and growth inhibition could not be correlated. The ten most antiproliferative compounds were tested for their hemolytic activity on mouse erythrocytes. Five compounds showing high antiproliferative activity and low hemolytic activity were thus identified for further study.


Assuntos
Alcenos/farmacologia , Divisão Celular/efeitos dos fármacos , Compostos Ferrosos/química , Hemólise/efeitos dos fármacos , Neoplasias/patologia , Espécies Reativas de Oxigênio/metabolismo , Alcenos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Metalocenos , Neoplasias/metabolismo , Espectrofotometria Infravermelho
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