RESUMO
Hydro-distilled essential oil from leaves of Xylopia laevigata was characterized by GC-MS. Twenty-seven components were identified and the oil's major constituents comprised germacrene D, bicyclogermacrene, (E)-caryophyllene and germacrene B. The cytotoxicity of the essential oil of X. laevigata (EOXL), determined by MTT and mitotic index methods in cultured human lymphocytes was observed in all tested concentrations. Cultures treated with EOXL demonstrated significant increase in the frequencies of micronuclei in the cytokinesis-block micronucleus assay (CBMN) and reduction of the cytokinesis-block proliferation index (CBPI) rates. Results demonstrated the cytostatic and mutagenic effects of EOXL, the latter for the first time.
Assuntos
Citostáticos/farmacologia , Linfócitos/efeitos dos fármacos , Mutagênicos/farmacologia , Óleos Voláteis/farmacologia , Xylopia/química , Células Cultivadas , Citostáticos/química , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Linfócitos/fisiologia , Testes para Micronúcleos , Mutagênicos/química , Óleos Voláteis/química , Óleos Voláteis/toxicidade , Folhas de Planta/química , Plantas Medicinais/química , Sesquiterpenos Policíclicos/análise , Sesquiterpenos de Germacrano/análiseRESUMO
Drug resistance in the treatment of neglected parasitic diseases, such as leishmaniasis and trypanosomiasis, has led to the search and development of alternative drugs from plant origins. In this context, the essential oil extracted by hydro-distillation from Lantana camara leaves was tested against Leishmania braziliensis and Trypanosoma cruzi. The results demonstrated that L. camara essential oil inhibited T. cruzi and L. braziliensis with IC50 of 201.94 µg/mL and 72.31 µg/mL, respectively. L. camara essential oil was found to be toxic to NCTC929 fibroblasts at 500 µg/mL (IC50 = 301.42 µg/mL). The composition of L. camara essential oil analyzed by gas chromatography-mass spectrometry (GC/MS) revealed large amounts of (E)-caryophyllene (23.75%), biciclogermacrene (15.80%), germacrene D (11.73%), terpinolene (6.1%), and sabinene (5.92%), which might be, at least in part, responsible for its activity. Taken together, our results suggest that L. camara essential oil may be an important source of therapeutic agents for the development of alternative drugs against parasitic diseases.
Assuntos
Lantana/química , Leishmania/efeitos dos fármacos , Óleos Voláteis/análise , Óleos Voláteis/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citostáticos/análise , Citostáticos/química , Citostáticos/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Camundongos , Óleos Voláteis/química , Folhas de Planta/químicaRESUMO
Two new diterpenoid α-pyrones, named higginsianins A (1) and B (2), were isolated from the mycelium of the fungus Colletotrichum higginsianum grown in liquid culture. They were characterized as 3-[5a,9b-dimethyl-7-methylene-2-(2-methylpropenyl)dodecahydronaphtho[2,1-b]furan-6-ylmethyl]-4-hydroxy-5,6-dimethylpyran-2-one and 4-hydroxy-3-[6-hydroxy-5,8a-dimethyl-2-methylene-5-(4-methylpent-3-enyl)decahydronaphthalen-1-ylmethyl]-5,6-dimethylpyran-2-one, respectively, by using NMR, HRESIMS, and chemical methods. The structure and relative configuration of higginsianin A (1) were confirmed by X-ray diffractometric analysis, while its absolute configuration was assigned by electronic circular dichroism (ECD) experiments and calculations using a solid-state ECD/TDDFT method. The relative and absolute configuration of higginsianin B (2), which did not afford crystals suitable for X-ray analysis, were determined by NMR analysis and by ECD in comparison with higginsianin A. 1 and 2 were the C-8 epimers of subglutinol A and diterpenoid BR-050, respectively. The evaluation of 1 and 2 for antiproliferative activity against a panel of six cancer cell lines revealed that the IC50 values, obtained with cells reported to be sensitive to pro-apoptotic stimuli, are by more than 1 order of magnitude lower than their apoptosis-resistant counterparts (1 vs >80 µM). Finally, three hemisynthetic derivatives of 1 were prepared and evaluated for antiproliferative activity. Two of these possessed IC50 values and differential sensitivity profiles similar to those of 1.
Assuntos
Colletotrichum/química , Citostáticos/isolamento & purificação , Citostáticos/farmacologia , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Pironas/isolamento & purificação , Pironas/farmacologia , Animais , Dicroísmo Circular , Citostáticos/química , Diterpenos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Pironas/química , Estereoisomerismo , Relação Estrutura-Atividade , Trinidad e TobagoRESUMO
The venom of amphibians is a fascinating source of active substances. In view of their medical importance and aiming to explore the amazing Brazilian biodiversity, we conducted bioprospecting of antiproliferative activity in extracts of Rhinella marina and Rhaebo guttatus toads occurring in the Southern Amazon of Mato Grosso, Brazil. LC-MS and HPLC analysis of the venom extracts of R. marina revealed four bufadienolides (telocinobufagin, marinobufagin, bufalin and resibufogenin. R. guttatus venom extracts contained only marinobufagin. First, R. marina and R. guttatus venom extracts were evaluated for cytotoxicity against tumor cell lines by the MTT assay. All extracts revealed cytotoxicity, where R. marina extracts were comparable to doxorubicin (IC50 values ranging from 0.01 to 0.23 µg/mL). Only extracts of R. guttatus toad venom caused membrane disruption of human erythrocytes. The extracts were investigated for selective activity by determining their effect on stimulated human peripheral blood mononuclear cells (PBMC) with the Alamar Blue™ assay. The extracts were up to 80-fold more selective against leukemia cells when compared to dividing leukocytes. Aiming to confirm these antiproliferative effects, BrdU incorporation into DNA was measured in HL-60 treated cells with R. marina venom extracts. These extracts decreased BrdU incorporation at both concentrations tested. In summary, nine extracts of R. marina and R. guttatus venom showed pronounced lethal and discriminating effects on tumor lines, especially those from R. marina, highlighting toad parotoid gland secretions as a promising source for novel lead anticancer chemicals.
Assuntos
Venenos de Anfíbios/farmacologia , Bufonidae , Citostáticos/farmacologia , Venenos de Anfíbios/química , Animais , Brasil , Linhagem Celular Tumoral , Citostáticos/química , Citostáticos/isolamento & purificação , Células HL-60 , Humanos , Leucócitos Mononucleares/efeitos dos fármacosRESUMO
Cytostatics are a major class of chemotherapy drugs with great potential to cause genotoxic and/or mutagenic effects in all organisms. Currently, hospital wastewater treatment systems (HWTS) are not able to remove these compounds and they are discharged to the environment. Thus, the objective of this study was to investigate the oxidative degradation of the cytostatic drugs doxorubicin (DOXO) [(8s,10s)-10-(4-amino-5-hydroxy-6-methyl-tetrahydro-2h-pyran-2-yloxy)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione] and methotrexate (METHO) {N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid} by ozonolysis alone and using a combined sonolysis/ozonolysis process on bench-scale at different pH values. Besides determining the degradation efficiency, a kinetic approach was applied to determine the reaction order and rate constants for different oxidative processes carried out at pH 7.0, which is the normal pH of hospital wastewater. The results showed that the removal efficiency of these compounds is pH-dependent. A combination of sonolysis and ozonolysis processes is more efficient than the ozonolysis process alone for the degradation of doxorubicin at all pH values, while methotrexate can easily be degraded by ozonolysis alone or sonolysis/ozonolysis methodologies at any pH.
Assuntos
Doxorrubicina/química , Metotrexato/química , Eliminação de Resíduos Líquidos/métodos , Poluentes Químicos da Água/química , Citostáticos/química , Cinética , Ozônio/química , UltrassonografiaRESUMO
One new (1) and three known (2-4) isonitrile diterpenes, isolated from the Caribbean sponge Pseudoaxinella flava, were assayed in human cancer cell lines in vitro using an MTT colorimetric assay and quantitative videomicroscopy. Compounds 1-4 displayed activity for human PC3 prostate apoptosis-sensitive cancer cell lines. Compounds 3 and 4 demonstrated similar growth inhibitory effects for three apoptosis-sensitive and three apoptosis-resistant cancer cell lines. Quantitative videomicroscopy analysis revealed that compounds 1 and 2 exerted their activity through cytotoxic effects, and compounds 3 and 4 through cytostatic effects. These results identify marine diterpene isonitriles as potential lead compounds for anticancer drug discovery.
Assuntos
Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Citostáticos/isolamento & purificação , Citostáticos/farmacologia , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Nitrilas/isolamento & purificação , Nitrilas/farmacologia , Poríferos/química , Animais , Antineoplásicos/química , Bahamas , Região do Caribe , Citostáticos/química , Diterpenos/química , Humanos , Masculino , Microscopia de Vídeo , Estrutura Molecular , Nitrilas/química , Neoplasias da Próstata/tratamento farmacológicoRESUMO
We have shown that Benznidazole (BZL), a compound with well documented trypanocidal activity, possesses anti-inflammatory properties and inhibits the nuclear factor kappaB (NF-kappaB). Given the relationship between this transcription factor and cell growth, in this study we address the role of NF-kappaB blockade by BZL in the proliferation of different cell lines. Our studies demonstrate that this compound significantly reduced proliferation of RAW 264.7 macrophage cell line, as assessed by trypan blue exclusion, MTT reduction and [(3)H]-thymidine incorporation, at a concentration shown to inhibit NF-kappaB. Treatment with BZL also led to growth arrest in CHO, MDCK and HeLa cells. Interestingly, growth inhibition was found to be a reversible process, not accompanied by significant cell death, indicating that the drug behaves mainly as a cytostatic compound. As this effect might be related to NF-kappaB inhibition, we next evaluated whether other NF-kappaB inhibitors could induce growth arrest in RAW 264.7 and HeLa cells. We found that IKK inhibition led to growth arrest in both cell lines, indicating that NF-kappaB inhibition may be the potential mechanism by which BZL inhibits cell proliferation. To the best of our knowledge, this is the first report of an anti-proliferative activity of the trypanocidal drug against different cell lines and provides a mechanistic insight that may help understand some of the adverse effects associated with prolonged treatment.
Assuntos
Proliferação de Células/efeitos dos fármacos , Citostáticos/farmacologia , Nitroimidazóis/farmacologia , Tripanossomicidas/farmacologia , Animais , Células CHO , Linhagem Celular , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Citostáticos/química , Cães , Células HeLa , Humanos , Leupeptinas/farmacologia , Camundongos , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Nitrilas/farmacologia , Nitroimidazóis/química , Sulfonas/farmacologia , Tripanossomicidas/químicaRESUMO
This study consists of the bioassay-guided fractionation of the dichloromethane extract from Eudistoma vannamei and the pharmacological characterization of the active fractions. The dried hydromethanolic extract dissolved in aqueous methanol was partitioned with dichloromethane and chromatographed on a silica gel flash column. The anti-proliferative effect was monitored by the MTT assay. Four of the latest fractions, numbered 14 to 17, which held many chemical similarities amongst each other, were found to be the most active. The selected fractions were tested for viability, proliferation and death induction on cultures of HL-60 promyeloblastic leukemia cells. The results suggested that the observed cytotoxicity is related to apoptosis induction.