RESUMEN
Artelastin, a novel prenylated flavone, previously isolated from the wood bark of Artocarpus elasticus, was evaluated for its capacity to inhibit the growth of fifty-two human tumor cell lines, representing nine different tumor types. A pronounced dose-dependent growth inhibitory effect was detected in all the cell lines, with GI50 values ranging from 0.8-20.8 microM. Studies to elucidate the basis of the growth inhibitory activity of artelastin were performed in the MCF-7 human breast cancer cell line (GI50 = 6.0 microM). We show that artelastin exerts a biphasic effect in the DNA synthesis of MCF-7 cells, a stimulatory effect at low concentrations (below GI50) for short times of exposition (6 h and 24 h), and an inhibitory effect at high concentrations (above GI50). Remarkably, treated cells that have DNA synthesis affected could be viable and metabolically active. Furthermore, artelastin acts as a cytotoxic rather than a cytostatic compound. Massive cytoplasmatic vacuoles were detected in cells after artelastin treatment. Together with these morphological alterations, cells show the presence of abnormal nuclear morphologies, and occasionally nuclear condensation, which were identified as apoptotic by TUNEL assay. Moreover, artelastin was shown to disturb the microtubule network while no effect was observed on the kinetochores. Flow cytometry analysis of cells treated with artelastin reveal an accumulation in S phase that interferes with the cell cycle progression. Additionally, according to BrdU patterns, studies with synchronized cells at G0 and at G1/S transition also suggest that artelastin delays DNA replication since progression of cells trough S-phase is perturbed.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Flavonoides/farmacología , Microtúbulos/efectos de los fármacos , Extractos Vegetales/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/metabolismo , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Forma de la Célula , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Flavonoides/química , Flavonoides/metabolismo , Humanos , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/metabolismoRESUMEN
Six known lupanes lupenone ( 1), 3- epi-lupeol ( 2), glochidone ( 4), glochidonol ( 5), glochidiol ( 6) and lup-20(29)-ene-1beta,3beta-diol ( 7) were isolated from the roots and stem wood of Glochidion eriocarpum and three, 5, 6 and lup-20(29)ene-3alpha,23-diol ( 3), were isolated from the roots and stem wood of Glochidion sphaerogynum. Compounds were identified by (1)H- and (13)C-NMR techniques. Triterpenes 2 - 7 were tested against the growth of three human tumor cell lines, MCF-7, NCI-H-460 and SF-268. Lupanes 3, 5, and 6 exhibited strong inhibitory effects against all three; thus GI (50) values for 3 were 12.7 +/- 3.7, 17.9 +/- 1.1 and 17.9 +/- 0.5, for 5 9.0 +/- 3.7, 4.9 +/- 0.2 and 9.8 +/- 0.5, and for 6 6.63 +/- 0.7, 7.5 +/- 0.5 and 9.7 +/- 0.3.3. Epilupeol was less active, with GI (50) values of 75.6 +/- 11.7, 86.1 +/- 12.4 and 80.9 +/- 2.6 while 7 was moderately active only against MCF-7 (GI (50) = 79.2 +/- 2.4). Additional studies indicated that triterpenes 5 and 6 exerted their antiproliferative activity through the involvement of apoptosis while triterpene 3 did not.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Phyllanthus , Fitoterapia , Extractos Vegetales/farmacología , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/uso terapéutico , Línea Celular Tumoral/efectos de los fármacos , Humanos , Extractos Vegetales/administración & dosificación , Extractos Vegetales/uso terapéutico , Raíces de Plantas , Tallos de la Planta , Triterpenos/administración & dosificación , Triterpenos/química , Triterpenos/farmacología , Triterpenos/uso terapéuticoRESUMEN
A new jatrophane diterpene, pubescenol (1), known ent-abietane lactones, helioscopinolide A (2) and B (3), and taraxerone, 24-methylenecycloartanol, and vanillin have been isolated from Euphorbia pubescens. Diterpenes 1-3 and previously described pubescene D (4) were shown to be moderate inhibitors of the growth of MCF-7, NCI-H460, and SF-268 human tumor cell lines, whereas compounds 2 and 3 also exhibited significant antibacterial activity against Staphylococcus aureus.
Asunto(s)
Abietanos/aislamiento & purificación , Antibacterianos/aislamiento & purificación , Antineoplásicos Fitogénicos/aislamiento & purificación , Diterpenos/aislamiento & purificación , Euphorbia/química , Plantas Medicinales/química , Abietanos/química , Abietanos/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Diterpenos/química , Diterpenos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Portugal , Staphylococcus aureus/efectos de los fármacos , Estereoisomerismo , Células Tumorales CultivadasRESUMEN
Three new macrocyclic jatrophane diterpene polyesters, named pubescenes A ( 1), B ( 2), and C ( 3), and the known compounds indole-3-aldehyde and scopoletin have been isolated and characterised from the whole dried plant of Euphorbia pubescens. The structures of the new compounds were established by spectroscopic means including 2D-NMR techniques such as COSY, HMQC, HMBC and NOESY experiments. Compounds 1 - 3 were evaluated for their in vitro effect on the growth of three human cancer cell lines MCF-7 (breast), NCI-H460 (lung) and SF-268 (CNS) as well as for their capacity to interfere with the proliferation of human peripheral blood lymphocytes. They exhibited a moderate growth inhibitory effect on the cancer cell line NCI-H460. No effect was observed on the mitogenic response of human lymphocytes to PHA.
Asunto(s)
Antineoplásicos/farmacología , Diterpenos/farmacología , Euphorbia , Fitoterapia , Extractos Vegetales/farmacología , Antineoplásicos/administración & dosificación , Diterpenos/administración & dosificación , Humanos , Linfocitos/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
Clionasterol (1a), clionasterol monoacetate (1b) and 5alpha,8alpha-epidioxy-24alpha-ethylcholest-6-en-3-ol (2), isolated from the marine sponge Xestospongia exigua, and beta-sitosterol (3) were tested for their influence on the classical (CP) and alternative (AP) pathways of activation of the human complement system in vitro. All the sterols inhibited the CP in a dose-dependent manner but no detectable effect was observed in the AP even at concentrations of 400 microM. Clionasterol was found to be a potent inhibitor of CP (IC50 = 4.1 microM) being ten-fold more active than beta-sitosterol. The presence of the epidioxy group on C-5 and C-8 of compound 2 caused a pronounced decrease of the inhibitory effect. Mechanistic studies on the anticomplementary effect of clionasterol revealed that it interferes with the complement component C1.
Asunto(s)
Proteínas Inactivadoras de Complemento/farmacología , Poríferos , Sitoesteroles/farmacología , Animales , Proteínas Inactivadoras de Complemento/administración & dosificación , Proteínas Inactivadoras de Complemento/uso terapéutico , Vía Alternativa del Complemento/efectos de los fármacos , Vía Clásica del Complemento/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Hemólisis/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Sitoesteroles/administración & dosificación , Sitoesteroles/uso terapéuticoRESUMEN
Five known abietane diterpenes, fatty acid esters of 7alpha-acyloxy-6beta-hydroxyroyleanone (1), grandidone A (2), 7alpha-acetoxy-6beta-hydroxyroyleanone (3), 6beta,7alpha-dihydroxyroyleanone (4), and coleon U (5), isolated from Plectranthus grandidentatus Gürke, were evaluated for their in vitro antiproliferative activity against five human cancer cell lines MCF-7, NCI-H460, SF-268, TK-10, and UACC-62. Coleon U (5) exhibited the strongest effect among all the assayed compounds. The abietane 3 revealed also a strong inhibitory effect while diterpenes 2 and 4 inhibited only slightly the growth of all cancer cell lines.