RESUMEN
Vanadium compounds were studied during recent years to be considered as a representative of a new class of nonplatinum metal antitumor agents in combination to its low toxicity. On the other hand, flavonoids are a wide family of polyphenolic compounds synthesized by plants that display many interesting biological effects. Since coordination of ligands to metals can improve the pharmacological properties, we report herein, for the first time, a exhaustive study of the mechanisms of action of two oxidovanadium(IV) complexes with the flavonoids: silibinin Na2[VO(silibinin)22]·6H2O (VOsil) and chrysin [VO(chrysin)2EtOH]2(VOchrys) on human colon adenocarcinoma derived cell line HT-29. The complexes inhibited the cell viability of colon adenocarcinoma cells in a dose dependent manner with a greater potency than that the free ligands and free metal, demonstrating the benefit of complexation. The decrease of the ratio of the amount of reduced glutathione to the amount of oxidized glutathione were involved in the deleterious effects of both complexes. Besides, VOchrys caused cell cycle arrest in G2/M phase while VOsil activated caspase 3 and triggering the cells directly to apoptosis. Moreover, VOsil diminished the NF-kB activation via increasing the sensitivity of cells to apoptosis. On the other hand, VOsil inhibited the topoisomerase IB activity concluding that this is important target involved in the anticancer vanadium effects. As a whole, the results presented herein demonstrate that VOsil has a stronger deleterious action than VOchrys on HT-29 cells, whereby suggesting that Vosil is the potentially best candidate for future use in alternative anti-tumor treatments.
Asunto(s)
Neoplasias del Colon/tratamiento farmacológico , Complejos de Coordinación/química , Flavonoides , Silimarina , Vanadio , Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Complejos de Coordinación/farmacología , Flavonoides/química , Humanos , Estructura Molecular , Silibina , Silimarina/química , Vanadio/químicaRESUMEN
Polyoxometalates (POMs) are early transition metal oxygen anion clusters. They display interesting biological effects mainly related to their antiviral and antitumor properties. On the other hand, copper compounds also show different biological and pharmacological effects in cell culture and in animal models. We report herein for the first time, a detailed study of the mechanisms of action of a copper(II) compound of the group of HPOMs with the formula K7Na3[Cu4(H2O)2(PW9034)2]20H2O (PW9Cu), in a model of human osteosarcoma derived cell line, MG-63. The compound inhibited selectively the viability of the osteosarcoma cells in the range of 25-100µM (p<0.01). Besides, we have clearly shown a more deleterious action of PW9Cu on tumor osteoblasts than in normal cells. Cytotoxicity studies also showed deleterious effects for PW9Cu. The increment of reactive oxygen species (ROS) and the decrease of the GSH/GSSG ratio were involved in the antiproliferative effects of PW9Cu. Moreover, the compound caused cell cycle arrest in G2 phase, triggering apoptosis as determined by flow cytometry. As a whole, these results showed the main mechanisms of the deleterious effects of PW9Cu in the osteosarcoma cell line MG-63, demonstrating that this compound is a promissory agent for cancer treatments.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Óseas/tratamiento farmacológico , Complejos de Coordinación/farmacología , Cobre/farmacología , Osteosarcoma/tratamiento farmacológico , Óxidos/farmacología , Compuestos de Tungsteno/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/química , Cobre/química , Fragmentación del ADN , Glutatión/metabolismo , Humanos , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Osteosarcoma/metabolismo , Osteosarcoma/patología , Estrés Oxidativo/efectos de los fármacos , Óxidos/química , Fosfatidilserinas/metabolismo , Compuestos de Tungsteno/químicaRESUMEN
Cestodes show a remarkable proliferative capability that sustains the constant growth and differentiation of proglottids essential for their lifestyle. It is believed that a separate population of undifferentiated stem cells (the so-called germinative cells) are the only cells capable of proliferation during growth and development. The study of this particular cell subpopulation is hampered by the current lack of methods to isolate it. In this work, we developed a reproducible flow cytometry and cell sorting method to quantify and isolate the proliferating cells in the tetrathyridia larvae of the model cestode Mesocestoides corti, based on the DNA content of the cells. The isolated cells display the typical germinative cell morphology, and can be used for RNA isolation with a yield in the ng to µg range. We expect that this approach may facilitate the characterization of the germinative cells in M. corti and other model tapeworms.
Asunto(s)
Separación Celular/métodos , Citometría de Flujo/métodos , Mesocestoides/citología , Animales , Bencimidazoles , Ciclo Celular , Proliferación Celular , Fluoresceínas , Colorantes Fluorescentes , Indicadores y Reactivos , Larva/citología , Mesocestoides/crecimiento & desarrollo , Ratones , Modelos Animales , Propidio , Reproducibilidad de los Resultados , Tripsina/metabolismoRESUMEN
Flavonoids, a polyphenolic compound family, and the vanadium compounds have interesting biological, pharmacological, and medicinal properties. We report herein the antitumor actions of the complex [VO(chrysin)2EtOH]2 (VOchrys) on the MG-63 human osteosarcoma cell line. Oxovanadium(IV), chrysin and VOchrys caused a concentration-dependent inhibition of cell viability. The complex was the strongest antiproliferative agent (p < 0.05). Cytotoxicity and genotoxicity studies also showed a concentration effect. Reactive oxygen species (ROS) and the alterations in the GSH/GSSG ratio underlie the main mechanisms of action of VOchrys. Additions of ROS scavengers (vitamin C plus vitamin E) or GSH to the viability experiments demonstrated beneficial effects (p < 0.01). Besides, the complex triggered apoptosis, disruption of the mitochondria membrane potential (MMP), increased levels of caspase 3 and DNA fragmentation measured by the sub-G1 peak in cell cycle arrest experiments (p < 0.01). Collectively, VOchrys is a cell death modulator and a promissory complex to be used in cancer treatments.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Flavonoides/química , Compuestos Organometálicos/farmacología , Osteosarcoma/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Vanadatos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Osteosarcoma/patología , Relación Estructura-ActividadRESUMEN
Chromosome breakpoints induced by neutrons or gamma rays in Chinese hamster ovary cells were mapped to Giemsa-light or Giemsa-dark bands or to band junctions. Radiation-induced breakpoints were found to be distributed nonrandomly according to chromosome or band length. More than 60% of the breakpoints were localized in G-light bands. A group of 13 bands which corresponded to only 7% of the total chromosome length contained 22% of the breakpoints produced by neutrons and 14% of those induced by gamma rays. Seven of these 13 bands are also preferentially damaged by AluI, BamHI and DNase I as reported previously. The results indicate that chromatin and nuclear structure may play a role in the distribution of breakpoints produced by ionizing radiation and endonucleases.