RESUMO
Cucurbitacins are a wide group of natural products found in several plant families, especially in the Cucurbitaceae family. In the last decade, there has been a significant increase in studies aimed at identifying new biological activities of cucurbitacins and describing their mechanisms of action. The most researched pharmacological activities are antineoplastic and anti-inflammatory activity, the first being recently reviewed. The present review explains the anti-inflammatory, antioxidant, and immunomodulatory potential of cucurbitacins, identifying the most studied compounds in this area and exploring their mechanisms of action already studied. A brief report was made about the main structural characteristics of cucurbitacins, in addition to an update on the biological activities attributed to this class in the last 5 years. Cucurbitacin B and cucurbitacin E have been identified as the most investigated when it comes to the immune response, playing roles in both innate and adaptive immunity. The most cited mechanisms were inhibition of COX-2 and NOS, reduction of oxidative stress, suppression of proinflammatory cytokines and modulation of acquired immunity proteins. It was found that cucurbitacins are promising molecules in the search for therapeutic innovation and have wide versatility in the immune response.
Assuntos
Cucurbitacinas , Triterpenos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Cucurbitacinas/química , Cucurbitacinas/farmacologia , Cucurbitacinas/uso terapêutico , Humanos , Sistema Imunitário , Imunidade , Triterpenos/farmacologia , Triterpenos/uso terapêuticoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The tea made with the fruits of Luffa operculata (L.) Cogn. (Cucurbitaceae; EBN) is popularly used as abortive. AIM OF THE STUDY: The present work aimed at accessing how the exposition of female Wistar rats to 1.0 mg/kg of EBN (experimental group, EG), or distilled water (control group, CG), by gavage, at gestational days (GD) 17-21 interfered with the reproductive performance, and with dams' behavior after weaning. MATERIALS AND METHODS: At post-natal day 2 (PND2), the number of male and female pups was evaluated, as well as their weight. After weaning (PND21), dams were euthanized, and their liver and kidneys were removed for histological and biochemical analyses, while the blood was used in the evaluation of cytokines IL-1α, IL-1ß, IL-6 and TNF-α, corticosterone, adrenocorticotrophic hormone, melatonin, AST, ALT and creatinine levels. RESULTS AND DISCUSSION: Dams that were treated with EBN showed an anxiety-like behavior, weight loss at the end of gestation and weight gain at weaning, accompanied with a significant decrease in pro-inflammatory cytokines and in the melatonin level. No significant histological or biochemical alterations have occurred in the liver or kidneys. The number of female pups was significantly higher in the EG. The male pups showed weight gain at PND60. CONCLUSION: The presence of cucurbitacins is probably involved in the dysregulations that were found, due to their polycyclic steroid triterpene structure.
Assuntos
Citocinas/sangue , Luffa/química , Melatonina/sangue , Extratos Vegetais/farmacologia , Administração Oral , Hormônio Adrenocorticotrópico/sangue , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Corticosterona/sangue , Cucurbitacinas/química , Cucurbitacinas/farmacologia , Cucurbitacinas/toxicidade , Feminino , Frutas/química , Hormônios/sangue , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Masculino , Exposição Materna , Extratos Vegetais/administração & dosagem , Extratos Vegetais/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos Wistar , Reprodução/efeitos dos fármacos , Caracteres SexuaisRESUMO
Bioprospecting identifies new sources of compounds with actual or potential economic value that come from biodiversity. An analysis was performed regarding bioprospecting purposes in ten genotypes of Sechium spp., through a meta-analysis of 20 information sources considering different variables: five morphological, 19 biochemical, anti-proliferative activity of extracts on five malignant cell lines, and 188 polymorphic bands of amplified fragment length polymorphisms, were used in order to identify the most relevant variables for the design of genetic interbreeding. Significant relationships between morphological and biochemical characters and anti-proliferative activity in cell lines were obtained, with five principal components for principal component analysis (SAS/ETS); variables were identified with a statistical significance (< 0.7 and Pearson values ≥ 0.7), with 80.81% of the accumulation of genetic variation and 110 genetic bands. Thirty-nine (39) variables were recovered using NTSYSpc software where 30 showed a Pearson correlation (> 0.5) and nine variables (< 0.05), Finally, using a cladistics analysis approach highlighted 65 genetic bands, in addition to color of the fruit, presence of thorns, bitter flavor, piriform and oblong shape, and also content of chlorophylls a and b, presence of cucurbitacins, and the IC50 effect of chayote extracts on the four cell lines.
Assuntos
Bioprospecção , Cucurbitaceae , Cucurbitacinas/farmacologia , Frutas/química , Extratos Vegetais/farmacologia , Animais , Linhagem Celular , Cucurbitaceae/química , Cucurbitaceae/classificação , Cucurbitaceae/genética , Genótipo , Humanos , Camundongos , Polimorfismo GenéticoRESUMO
BACKGROUND: Cucurbitacin IIb (CIIb) from Ibervillea sonorae has a high capacity to suppress cancer cell proliferation and induce apoptosis. This study investigated the molecular mechanisms related to the antiproliferative and apoptosis induction capacity of CIIb in HeLa cells. MATERIALS AND METHODS: The cell viability and anti-proliferative effect of CIIb were evaluated by using the trypan blue exclusion assay. The effect of CIIb on the mitochondrial membrane potential was determined by flow cytometry using JC-1. The activity of caspase-3 and caspase-9 was evaluated by flow cytometry using commercial kits. The effect of CIIb on the cell cycle was investigated using Fluorescence-Activated Cell Sorting (FACS) analysis. Western blot analysis was used to evaluate both the inhibitory effect of CIIb on the STAT3 signaling pathway and cyclin -B1, and DNA damage by the comet assay. RESULTS: CIIb triggers disruption of the mitochondrial membrane potential (Δψm) and consequently activated the caspases -3 and -9, as a result of the activation of the intrinsic pathway of the apoptosis. Likewise, the CIIbinduced cell cycle was arrested in S and G2/M after 24h of treatment. CIIb also reduced the expression of STAT3 and cyclin -B1. Finally, CIIb produced an antiproliferative effect at 48 and 72 h, inducing DNA damage. CONCLUSION: These results demonstrate CIIb-induced apoptosis and cell cycle arrest in HeLa through the inhibition of STAT3.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Cucurbitaceae/química , Cucurbitacinas/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cucurbitacinas/química , Cucurbitacinas/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Estrutura Molecular , Fator de Transcrição STAT3/metabolismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Chemical studies on Ibervillea sonorae (S. Watson) Greene root led to isolation and chemical characterization of diverse cucurbitacin triterpenoid compounds such as kinoin A, B, C, and their glucosides. In previous studies, we demonstrated that kinoin A inhibits the cell proliferation on diverse cell line and induce apoptosis in HeLa cells. Therefore, the study of the isolated compounds from the extracts continued to be necessary. The objective of the present work was to isolate and chemically characterize the active compounds of the methanolic extract of the roots of I. sonorae and to evaluate their antiproliferative activity and induction of apoptosis. By chromatographic column separation and using NMR spectroscopy experiments, cucurbitacin IIb (CIIb), known as 23,24-dihydrocucurbitacin F or hemslecin B, was isolated and identified for the first time as a chemical constituent of the crude methanolic extract of this plant. The antiproliferative activity of CIIb was evaluated by MTT assay, and the apoptosis induction capacity was monitored by annexin V-FITC/propidium iodide using flow cytometry. CIIb showed a pronounced effect on the proliferation of HeLa and A549 tumor cells, with IC50 of 7.3 and 7.8 µM, respectively, but was less effective against L929 non-cancerous murine cell line. Apoptosis induction capacity of CIIb on HeLa and A549 was monitored by annexin V-FITC/propidium iodide using flow cytometry. Exposure of HeLa and A549 with CIIb (8 µM) for 24 h increased 56.9 and 52.3% respectively of the total apoptosis compared to the negative control (p < 0.005). CIIb, isolated for the first time from I. sonorae, showed antiproliferative activity against HeLa and A549 cell lines by inducing cell death by apoptosis.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Cucurbitacinas/farmacologia , Células A549 , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cucurbitacinas/química , Cucurbitacinas/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Camundongos , Conformação Molecular , Células RAW 264.7 , Relação Estrutura-AtividadeRESUMO
The Sechium edule Perla Negra cultivar is a recently-obtained biological material whose progenitors are S. edule var. nigrum minor and S. edule var. amarus silvestrys, the latter of which has been reported to have antiproliferative activity against the HeLa P-388 and L-929 cancer cell lines. The present study aimed to determine if the methanolic extract of the fruit of the Perla Negra cultivar had the same biological activity. The methanolic extract was phytochemically characterized by thin layer chromatography (TLC) and column chromatography (CC), identifying the terpenes and flavonoids. The compounds identified via high performance liquid chromatography (HPLC) were Cucurbitacins B, D, E, and I for the terpene fractions, and Rutin, Phlorizidin, Myricetin, Quercetin, Naringenin, Phloretin, Apigenin, and Galangin for the flavonoid fractions). Biological activity was evaluated with different concentrations of the methanolic extract in the HeLa cell line and normal lymphocytes. The methanolic extract inhibited the proliferation of HeLa cells (IC50 1.85 µg·mL-1), but the lymphocytes were affected by the extract (IC50 30.04 µg·mL-1). Some fractions, and the pool of all of them, showed inhibition higher than 80% at a concentration of 2.11 µg·mL-1. Therefore, the biological effect shown by the methanolic extract of the Perla Negra has some specificity in inhibiting tumor cells and not normal cells; an unusual feature among molecules investigated as potential biomedical agents.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Cucurbitaceae/química , Apigenina/farmacologia , Cucurbitacinas/farmacologia , Feminino , Flavanonas/farmacologia , Flavonoides/farmacologia , Frutas/química , Células HeLa , Humanos , Concentração Inibidora 50 , Floretina/farmacologia , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Quercetina/farmacologia , Rutina/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
Cucurbitacin E is a potential drug candidate due to its anticancer activity, recognition of its molecular targets, and synergism with other drugs used for cancer treatment. However, the use of cucurbitacin E in clinical practice is not possible because of important knowledge gaps in its preclinical and clinical pharmacokinetic characteristics. Cucurbitacin E is hydrolyzed to cucurbitacin I in plasma and in human liver microsomes. The aim of this study was to evaluate the population pharmacokinetics of cucurbitacin E and of its metabolite cucurbitacin I in rats. The method for the sequential analysis of cucurbitacins E and I in rat plasma was developed using LC-MS/MS. Plasma aliquots of 50µL were deproteinized with acetonitrile and clobazam was added as internal standard. The extracts were injected into an RP-18 column and eluted with a mobile phase consisting of a mixture of acetonitrile:water:methanol (32:35:33, v/v/v). The method was precise and accurate, showing linearity in the range of 1-100ng cucurbitacin E/mL plasma and of 0.4-200ng cucurbitacin I/mL plasma. The method was applied to the pharmacokinetic evaluation of cucurbitacin E administered intravenously to male Wistar rats (1mg/kg). Serial blood samples were collected up to 24h after administration. The plasma concentrations of cucurbitacin E were quantified up to 16h, while the plasma concentrations of cucurbitacin I remained below the limit of quantification. A population pharmacokinetic model was developed for cucurbitacin E using the NONMEM program, with adequate goodness of fit and predictive performance. The following pharmacokinetic parameters were obtained: release time of 0.45h, volume of distribution of 27.22L, clearance of 4.13L/h, and elimination half-life of 4.57h.
Assuntos
Cucurbitacinas/sangue , Animais , Cromatografia Líquida , Masculino , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Espectrometria de Massas em TandemRESUMO
Cucurbitacins and their derivatives are triterpenoids that are found in various plant families, and are known for their pharmacological and biological activities, including anti-cancer effects. Lung cancer represents a major public health problem, with non-small-cell lung cancer (NSCLC) being the most frequent and aggressive type of lung cancer. The objective of this work was to evaluate four cucurbitacins (CUCs) for their cytotoxic activity, effects on apoptosis induction, cell cycle progression, anti-migratory, and anti-invasive effects on the human NSCLC cell line (A549 cells). Our findings showed that these CUCs could suppress human NSCLC cell growth in vitro through their effects on the PI3Kinase and MAPK pathways, which lead to programmed cell death induction, as well as inhibition of cell migration and cell invasion. Additionally, these effects culminate in apoptosis induction and G2/M cell cycle arrest by modulating cyclin B1 expression, and in the mitigation of strategic steps of lung cancer metastasis, including migration and invasion of A549 cells. These results suggest that two natural (DDCB and CB) and two novel semisynthetic derivatives of cucurbitacin B (ACB and DBCB) could be considered as promising compounds with antitumor potential.
Assuntos
Apoptose/efeitos dos fármacos , Cucurbitacinas/farmacologia , Cucurbitacinas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Células A549 , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cucurbitacinas/química , Ciclina B1/metabolismo , Regulação para Baixo/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
This article describes structure-activity relationship (SAR/QSAR) studies on the cytotoxic activity in a human lung adenocarcinoma cell line (A549) of 43 cucurbitacin derivatives. Modeling was performed using the methods partial least squares with discriminant analysis (PLS-DA) and PLS. For both studies, the variables were selected using the ordered predictor selection (OPS) algorithm. The SAR study demonstrated that the presence or absence of cytotoxic activity of the cucurbitacins could be described using information derived from their chemical structures. The QSAR study displayed suitable internal and external predictivity, and the selected descriptors indicated that the observed activity might be related to electrophilic attack on cellular structures or genetic material. This study provides improves the understanding of the cytotoxic activity of cucurbitacins and could be used to propose new cytotoxic agents.
Assuntos
Antineoplásicos/química , Cucurbitacinas/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cucurbitacinas/farmacologia , Humanos , Concentração Inibidora 50 , Modelos Químicos , Análise Multivariada , Relação Quantitativa Estrutura-AtividadeRESUMO
Cucurbitacins are secondary metabolites that mediate insect plant interactions not only as allomones against generalists but also as kairomones for specialist herbivores. This study was undertaken to identify the potential of cucurbitacin derivatives as insect antifeedant agents. The antifeedant capacity against a Cucurbitaceae specialist [ Epilachna paenulata (Coleoptera: Coccinellidae)] and a polyphagous insect [ Pseudaletia adultera (Lepidoptera: Noctuidae)] was evaluated in preference tests in which the insects were given a choice between food plants either treated with the cucurbitacin derivatives or treated with the solvent. The activity was found not to be related to the basic cucurbitacin skeleton, as only 15 of the 28 tested cucurbitacin derivatives were active. Only one of the tested compounds was phagostimulant to the specialist insect (the hemissuccinate of 16-oxo-dihydrocucurbitacin B derivative), while all other active derivatives were deterrent against one of the insects (13 compounds) or both of them (3 compounds). Changes in ring A of the cucurbitacins, as well as in the side chain, modified the activity. As a general trend, when chemical modifications of the basic structure produced a change in activity, the response was opposite in both insects used as biodetectors, indicating that a selective variation in the activity may be achieved by chemical modifications of the cucurbitacin skeleton.
Assuntos
Besouros/fisiologia , Cucurbitaceae/química , Cucurbitacinas/farmacologia , Lepidópteros/efeitos dos fármacos , Lepidópteros/fisiologia , Extratos Vegetais/farmacologia , Animais , Besouros/efeitos dos fármacos , Cucurbitacinas/química , Comportamento Alimentar/efeitos dos fármacos , Estrutura Molecular , Especificidade da EspécieRESUMO
Análise de Investigação sobre a presença de cucurbitacinas em abobrinhas de tronco redondas (cucurbita pepo l.) e sua relação com casos de intoxicação alimentar. (AU)
Assuntos
Cucurbita pepo/análise , Cucurbitacinas/efeitos adversos , Cucurbitacinas/toxicidade , Análise de Alimentos/métodos , Doenças Transmitidas por Alimentos/patologiaRESUMO
Chemical investigation of the roots of Wilbrandia ebracteata Cogn. (Cucurbitaceae) led to the isolation of two new (1- 2) and four known (3- 6) cucurbitacins. Their structures were elucidated by NMR and MS and compared with related compounds. The in vitro cytotoxicity of isolated compounds was evaluated against RD, KB, HCT-8, and A549 cell lines showing strong activity.
Assuntos
Cucurbitaceae/química , Cucurbitacinas/farmacologia , Extratos Vegetais/química , Brasil , Linhagem Celular Tumoral , Sobrevivência Celular , Cromatografia Líquida de Alta Pressão , Cucurbitacinas/química , Cucurbitacinas/isolamento & purificação , Humanos , Medicina Tradicional , Estrutura Molecular , Raízes de Plantas/química , Plantas Medicinais , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Two new cucurbitane-type triterpenoids, 2beta,3beta,16alpha,20(R),25-pentahydroxy-9-methyl-19-norlanost-5-en-7,22-dione and 2beta,3beta,16alpha,20(R),25-pentahydroxy-9-methyl-19-norlanost-5-en-7,11,22-trione, were isolated from fruits of Cayaponia racemosa. The total (1)H and (13)C chemical shift assignment of these two closely related compounds is described, making use of one- and two-dimensional NMR techniques.
Assuntos
Cucurbitaceae/química , Frutas/química , Triterpenos/química , Isótopos de Carbono , Cucurbitacinas , Espectroscopia de Ressonância Magnética , Estrutura Molecular , PrótonsRESUMO
The structures of two new cucurbitacin glucosides designated opercurins A (1) and B (2), isolated from the fruit of Luffa operculata, have been confirmed by extensive spectroscopic investigation.
Assuntos
Luffa/química , Medicina Tradicional , Triterpenos/isolamento & purificação , Brasil , Cucurbitacinas , Glucosídeos/química , Glucosídeos/isolamento & purificação , Glucosídeos/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Triterpenos/química , Triterpenos/farmacologiaRESUMO
The anti-inflammatory and antinociceptive actions of the CH2Cl2 extract and semipurified fraction (F-III) from roots of Wilbrandia ebracteata Cogn. have been investigated in rats and mice. The CH2Cl2 extract (1-10 mg/kg, i.p.; ID50 5 mg/kg) and (3-30 mg/kg, p.o.; ID50 15 mg/kg) inhibited, in a dose-related manner, carrageenan-induced paw edema in rats. The subfraction (F-III) from CH2Cl2 extract and compounds isolated as cucurbitacin B and E also inhibited carrageenan-induced edema. The CH2Cl2 extract and F-III also exhibited significant analgesic action in acetic acid-induced pain in mice. In the formalin test, the CH2Cl2 extract (0.3-10 mg/kg, i.p.) and (3-30 mg/kg, p.o.) caused inhibition of the neurogenic (first phase) and inflammatory phase (second phase) of formalin-induced pain. However, the CH2Cl2 extract was more effective in relation to the second phase than in inhibition of the formalin-induced edema. These findings suggest that CH2Cl2 extract has potent anti-inflammatory and analgesic action and that F-III and cucurbitacin B and E may account for these actions.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Raízes de Plantas/química , Triterpenos/farmacologia , Analgésicos/isolamento & purificação , Animais , Anti-Inflamatórios não Esteroides/isolamento & purificação , Cucurbitacinas , Masculino , Camundongos , Ratos , Ratos Wistar , Triterpenos/isolamento & purificaçãoRESUMO
Cucurbitacins are known to produce cytotoxic and anticancer activities. Two novel norcucurbitacin glucosides (Wv1 and Wv2) have recently been isolated from a purified fraction obtained from the rhizome of Wilbrandia verticillata. The present study evaluates the cytotoxic and antitumour activities of these norcucurbitacins. We have found a regular cytotoxicity in KB cells (Cy50 = 12 micrograms/ml) as well as a significant inhibition in the Walker 256 carcinosarcoma growth (approximately 75%).
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma 256 de Walker/tratamento farmacológico , Fitoterapia , Triterpenos/uso terapêutico , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Brasil , Cucurbitacinas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células KB/efeitos dos fármacos , Plantas Medicinais/química , Ratos , Triterpenos/isolamento & purificaçãoRESUMO
The anti-inflammatory activity of a purified fraction of the rhizome of Wilbrandia (cf) verticillata, which contains two novel norcucurbitacin glucosides, is reported. The increase of vascular permeability induced by acetic acid in mice (N = 5) was inhibited 69% and 90% by 50 and 100 mg/kg of the purified fraction, po (P less than 0.01). Acetylsalicylic acid (200 mg/kg), po, inhibited the response by 62% under the same conditions (P less than 0.05). The purified fraction (100 mg/kg, po) also significantly inhibited paw swelling in the rat formaldehyde-induced arthritis model on 8 of 10 days and reduced the swelling by 63% on day 10. Dexamethasone (1 mg/kg, ip) was more effective than the extract under the same conditions. These data partially characterize the anti-inflammatory activity of the purified fraction from this plant which is used in Brazilian folk medicine for the treatment of arthritis and related disorders.