ABSTRACT
Introduction: Three vanadium complexes with orotic and glutamic acids, in their anion forms, were prepared and their in vitro cytotoxicity toward human lung fibroblasts (MRC-5), human hepatocellular carcinoma (HepG2) and human colorectal adenocarcinoma (Caco-2) are reported. Objective: Describe the synthesis and characterization of new vanadium complexes with orotic and glutamic acids, and test its antitumor activity against HepG2 and Caco-2. Method: The complexes were formulated as VO (oro), VO (α-glu) and VO (γ-glu) based on chemical, thermogravimetric analyses and infrared spectra. Results: Resazurin assay demonstrates its cytotoxicity against the HepG2 and Caco-2 cell lines with the IC50 ranging from 7.90 to 44.56 µmol.L-1. The cytotoxicity profiles indicate that the tumoral lines show more activity than the cells MRC-5, with selectivity indexes ranging from 1.58 to 8.96. Conclusion: The three complexes had better in vitro activity than cisplatin for both normal and cancer cell lines. The IC50 values are two to six times better for the cancer cell ines and five to seven times better for the normal cell lines. This study indicates that the complexes obtained are promising candidates for antitumor drugs.
Introdução: Foram preparados três complexos de vanádio com ácidos orótico e glutâmico, em suas formas aniônicas, e foi testada sua citotoxicidade in vitro para fibroblastos pulmonares humanos (MRC-5), carcinoma hepatocelular humano (HepG2) e adenocarcinoma colorretal humano (Caco-2). Objetivo: Descrever a síntese e caracterização de novos complexos de vanádio com ácidos orótico e glutâmico e testar sua atividade antitumoral contra HepG2 e Caco-2. Método: Os complexos foram formulados como VO (oro), VO (α-glu) e VO (γ-glu) com base em análises químicas, termogravimétricas e espectros no infravermelho. Resultados: O ensaio de resazurina demonstrou sua citotoxicidade contra as linhagens celulares HepG2 e Caco-2 com o IC50 variando de 7,90 a 44,56 µmol.L-1. Os perfis de citotoxicidade indicam que as linhas tumorais apresentam maior atividade que as células MRC-5, com índices de seletividade variando de 1,58 a 8,96. Conclusão: Os três complexos tiveram melhor atividade in vitro do que a cisplatina, tanto para linhagens celulares normais como cancerosas. Os valores de IC50 são de duas a seis vezes melhores para as linhagens celulares cancerosas e de cinco a sete vezes melhores para as linhagens celulares normais. Este estudo indica que os complexos obtidos são promissores candidatos a fármacos antitumorais.
Introducción: Tres complejos de vanadio con ácidos orótico y glutámico, en sus formas aniónicas, fueram preparados. Su citotoxicidad in vitro hacia los fibroblastos pulmonares humanos (MRC-5), el carcinoma hepatocelular humano (HepG2) y el adenocarcinoma colorrectal humano (Caco-2) son reportados. Objetivo: Los principales objetivos de este trabajo son describir la síntesis y caracterización de nuevos complejos de vanadio con ácidos orótico y glutámico y probar su actividad antitumoral contra el HepG2 y el Caco-2. Método: Los complejos fueron formulados como VO (oro), VO (α-glu) y VO (γ-glu) basados en análisis químicos, termogravimétricos y espectros infrarrojos. El ensayo de resazurina demuestra su citotoxicidad contra las líneas celulares HepG2 y Caco-2 con el IC50 que van de 7,90 a 44,56 µmol.L-1. Los perfiles de citotoxicidad indican que las líneas tumorales presentan mayor actividad que los MRC-5, con índices de selectividad que van de 1,58 a 8,96. Conclusión: Los tres complejos tuvieron mejor actividad in vitro que el cisplatino, tanto para líneas celulares normales como para líneas celulares cancerosas. Los valores del IC50 son de dos a seis veces mejores para las líneas celulares de cáncer y de cinco a siete veces mejores para las líneas celulares normales. Este estudio indica que los complejos obtenidos son candidatos prometedores para fármacos antitumorales.
Subject(s)
Humans , Orotic Acid/pharmacology , Vanadium Compounds/pharmacology , Glutamic Acid/pharmacology , Cell Line, Tumor/drug effects , In Vitro Techniques , Drug Screening Assays, Antitumor , Colorectal Neoplasms/drug therapy , Adenocarcinoma/drug therapy , Carcinoma, Hepatocellular/drug therapy , Cancer-Associated Fibroblasts/drug effects , Lung Neoplasms/drug therapy , Antineoplastic Agents/pharmacologyABSTRACT
Foram avaliados os efeitos tóxicos do metavanadato de sódio (MV), pentóxido de vanádio (PV) e sulfato de oxovanádio (SV), potenciais fármacos antidiabéticos, em embriões e adultos de zebrafish (Danio rerio). Os embriões foram expostos a concentrações de 10-1000µg/mL para avaliação da CL50 96h e seus efeitos teratogênicos. Os adultos foram expostos a 10 e 20µg/mL dos mesmos compostos para se avaliarem alterações comportamentais relacionadas à exposição química e à mortalidade. A CL50 96h foi de 22,48, 53,62 e 74,14µg/mL para MV, SV e PV, respectivamente. Houve 100% de mortalidade nas concentrações de 400-1000µg/mL dos três compostos. Os efeitos teratogênicos mais observados (P<0,05) nos embriões foram edemas de pericárdio e saco vitelínico. Foram constatados, nos animais adultos expostos aos compostos de vanádio, maior batimento opercular e congestão nos arcos branquiais. A exibição dos comportamentos Flutuar e Descansar nos adultos expostos foi significativa (P<0,05), como também a exibição do comportamento Respiração Aérea. Pode-se concluir que a exposição química aos compostos de vanádio causou efeitos tóxicos em embriões e adultos de zebrafish com alta mortalidade. Diante disso, o seu uso como potencial fármaco antidiabético deve ser mais bem estudado em razão do efeito tóxico dessas substâncias.(AU)
The toxic effects of sodium metavanadate (MV), vanadium pentoxide (PV) and oxovanadium sulfate (SV), potential antidiabetic drug, on embryos and adults of zebrafish (Danio rerio) were evaluated. Embryos were exposed to concentrations of 10-1000µg/mL for evaluation of 96-h LC50 and their teratogenic effects. Adults were exposed to 10 and 20µg/mL of the same compounds to evaluate behavioral changes related to chemical exposure and mortality. The 96-h LC50 were 22.48, 53.62, and 74.14µg/mL for MV, SV, and PV, respectively. Mortality of 100% was observed at the concentrations of 400-1000µg/mL of the three compounds. The teratogenic effects most observed (P<0.05) were pericardial and yolk sac edemas. Adult animals exposed to the vanadium compounds had higher opercular beats and congestion in the gill arches. The exhibition of behaviors Floating and Resting in the exposed adults was significant (P<0.05), as well as the Air breathing behavior. Chemical exposure to vanadium compounds caused toxic effects in embryos and adults of zebrafish with high mortality. In conclusion, its use as a potential antidiabetic drug should be better studied due to the toxic effect.(AU)
Subject(s)
Animals , Behavior, Animal , Biological Factors/toxicity , Vanadium Compounds/toxicity , Fishes/physiology , Embryo ResearchABSTRACT
<p><b>OBJECTIVE</b>To investigate the roles of cytochrome c (Cyt-c), caspase-9, and caspase-3 in pentavalent vanadium-induced neuronal apoptosis and to provide a basis for mechanism research.</p><p><b>METHODS</b>Neurons from rats aged 1-3 days were cultured and treated with vanadium pentoxide (V2O5) at 5, 10, or 20 mmol/L. Neuronal apoptosis was detected by TdT-mediated dUTP-biotin nick end labeling (TUNEL). The protein levels of Cyt-c, caspase-9, and caspase-3 were determined by Western blot.</p><p><b>RESULTS</b>Apoptosis bodies were detected in the nuclei of neurons by TUNEL. The number of neurons with apoptosis bodies increased with increasing dose of V2O5 The apoptosis index (AI) was significantly higher in the 10 and 20 mm/L exposure groups than in the control group (P < 0.05 or P < 0.01). Western blot showed that the protein expression levels of Cyt-c and caspase-3 significantly increased in the 5 mmol/L exposure group as compared with the control group (P < 0.05). In the 10 and 20 mmol/L exposure groups, the protein expression of Cyt-c, caspase-9, and caspase-3 all increased as compared with the control group (P < 0.01). Neuronal AI was positively correlated with Cyt-c, caspase-9, and caspase-3 (r = 0.954, P < 0.01; r = 0.938, P < 0.01; r = 0.943, P < 0.01).</p><p><b>CONCLUSION</b>Pentavalent vanadium may induce neuronal apoptosis. The protein expression of Cyt-c, caspase-9, and caspase-3 may play an important role in neuronal apoptosis induced by pentavalent vanadium.</p>
Subject(s)
Animals , Rats , Apoptosis , Caspase 3 , Metabolism , Caspase 9 , Metabolism , Cytochromes c , Metabolism , Neurons , Metabolism , Vanadium , Toxicity , Vanadium Compounds , ToxicityABSTRACT
Vanadium compounds are potent in controlling elevated blood glucose levels in experimentally induced diabetes. However the toxicity associated with vanadium limits its role as therapeutic agent for diabetic treatment. A vanadium compound sodium orthovanadate (SOV) was given to alloxan-induced diabetic Wistar rats in lower doses in combination with Trigonella foenum graecum, a well-known hypoglycemic agent used in traditional Indian medicines. The effect of this combination was studied on lens morphology and glucose metabolism in diabetic rats. Lens, an insulin-independent tissue, was found severely affected in diabetes showing visual signs of cataract. Alterations in the activities of glucose metabolizing enzymes (hexokinase, aldose reductase, sorbitol dehydrogenase, glucose-6-phosphate dehydrogenase) and antioxidant enzymes (glutathione peroxidase, glutathione reductase) besides the levels of related metabolites, [sorbitol, fructose, glucose, thiobarbituric acid reactive species (TBARS) and reduced glutathione (GSH)] were observed in the lenses from diabetic rats and diabetic rats treated with insulin (2 IU/day), SOV (0.6 mg/ml), T. f. graecum seed powder (TSP, 5%) and TSP (5%) in combination with lowered dose of vanadium SOV (0.2 mg/ml), for a period of 3 weeks. The activity of the enzymes, hexokinase, aldose reductase and sorbitol dehydrogenase was significantly increased whereas the activity of glucose-6-phosphate dehydrogenase, glutathione peroxidase and glutathione reductase decreased significantly in lenses from 3 week diabetic rats. Significant increase in accumulation of metabolites, sorbitol, fructose, glucose was found in diabetic lenses. TBARS measure of peroxidation increased whereas the levels of antioxidant GSH decreased significantly in diabetic condition. Insulin restored the levels of altered enzyme activities and metabolites almost to control levels. Sodium orthovanadate (0.6 mg/ml) and Trigonella administered separately to diabetic animals could partially reverse the diabetic changes, metabolic and morphological, while vanadate in lowered dose in combination with Trigonella was found to be the most effective in restoring the altered lens metabolism and morphological appearance in diabetes. It may be concluded that vanadate at lowered doses administered in combination with Trigonella was the most effective in controlling the altered glucose metabolism and antioxidant status in diabetic lenses, these being significant factors involved in the development of diabetic complications, that reflects in the reduced lens opacity.
Subject(s)
Analysis of Variance , Animals , Antioxidants/metabolism , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/drug therapy , Dose-Response Relationship, Drug , Drug Therapy, Combination , Enzymes/metabolism , Female , Lens, Crystalline/anatomy & histology , Phytotherapy , Plant Preparations/pharmacology , Rats , Rats, Wistar , Trigonella/chemistry , Vanadium Compounds/pharmacologyABSTRACT
Se estudia el vanadio en las aguas de pozos artesianos de la zona arsenical (Pampa Húmeda) de la provincia de Córdoba (Argentina), descubierto y bien estudiado en esas aguas por Bado en 1917. Se pone de relieve su coincidencia patológica con el arsénico en esas mismas aguas, arsénico que según Ayerza ocasiona lo que él llamó en publicación primigenia "Arsenicismo regional endémico (keratodermia y melanodermia combinadas)". La repetición constante durante muchos años de esos dos oligoelementos en los análisis bioquímicos de las aguas de bebida y la no referencia del vanadio en las manifestaciones clínicas del HACREA llaman la atención del autor. Se insiste en la diferencia que hay entre el HACREA y otros hidroarsenicismos del mundo; en el HACREA, a las características clínicas comunes se le agregan los muy frecuentes y múltiples carcinomas de todas las formas clínicas e histológicas, lo que haría suponer que el vanadio pudiera ser una condición de riesgo por una interacción química con el arsénico y en tal condición fuera un co-carcinógeno en el HACREA
Subject(s)
Humans , Arsenic/analysis , Carcinogens, Environmental/analysis , Vanadium , Vanadium Compounds , Ascorbic Acid/therapeutic use , Argentina , Arsenic/adverse effects , Carcinogens , Chronic Disease , Oceans and Seas , Surface Waters , Vanadium , Vanadium CompoundsABSTRACT
Smooth muscle contraction has a characteristic step-response with successive additions of stimulating compounds, and instant reversal on withdrawing the stimulus, indicative of an equilibrium situation wherein continuous, rapid reactions are occurring. Vanadium compounds, ortho- and meta-vanadates, decavanadate and peroxovanadate, were found to contract a variety of smooth muscles. Their actions were analyzed with respect to activation of receptors, increase in the intracellular calcium concentration, and increase in calmodulin-dependent myosin light chain phosphorylation leading to contraction. A new perspective of smooth muscle contractility has emerged from the studies with vanadium compounds suggesting control mechanisms involving phosphorylation for contraction and redox for relaxation.
Subject(s)
Animals , Ion Channels/drug effects , Membrane Potentials/drug effects , Muscle Contraction/drug effects , Muscle Proteins/metabolism , Muscle, Smooth/drug effects , Oxidation-Reduction , Phosphorylation , Receptors, Cell Surface/drug effects , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Vanadium Compounds/chemistryABSTRACT
Rats made severely diabetic by an i.v. injection of 50-55 mg/kg streptozotocin (STZ), 15 days later showed blood glucose > 500 mg/dl, quadrupled daily water intake and plasma insulin of 14 +/- 3 microU/ml, about 25 per cent that of normal rats. Subsequently, these rats in two groups, received 0.5-1 mg/ml vanadyl sulphate in base solution (vanadyl) orally (Group I) and base solution containing 50 mEq/1 NaCl (Group II). Since 90 days of vanadyl therapy could not decrease blood glucose of group I (420 +/- 10 mg/dl) to normal levels, euglycaemia was achieved for a period of two months by intraperitoneal (i.p.) injection of NPH insulin. The required daily doses of insulin in vanadyl-treated rats of group I (8 +/- 1 U/kg/day) were only 8 per cent of those in group II animals (103 +/- 7 U/kg/day). In conclusion, it seems that vanadyl per se cannot induce normoglycaemia in diabetic rats with very low plasma insulin levels, but can augment the sensitivity of peripheral tissues to insulin.
Subject(s)
Animals , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/metabolism , Drinking , Homeostasis , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Male , Rats , Streptozocin , Vanadium Compounds/therapeutic use , Weight LossABSTRACT
Rats were made partially diabetic by intravenous injection of 40 mg/kg body weight streptozotocin [STZ]. Diabetic rats received 50 mEq/l sodium chloride [base solution] as drinking water for one month and then divided into two groups. Group I rats only received base solution for another month whereas group II were switched to 0.5-1 mg/ml vanadyl sulphate [VS] in base solution. Two months after induction of diabetes another blood sample was taken and all rats were killed to save their pancreases for histopathologic evaluations. Blood glucose levels and fluid intake of group I rats were 550 +/- 15 mg/dl and 210 +/- 8 ml/day respectively. Their plasma insulin, however, decreased to 50% of normal control rats [27 +/- 3 microU/ml]. Blood glucose and water intake of group II rats declined to 185 +/- 7 mg/dl, 25 +/- 4 ml/day but plasma insulin rose to 47 +/- 5 microU/ml which were significantly different from the results obtained in group I. Although the central cells of Islets of Langerhans of untreated diabetic rats were shrunken or missing in the VS treated rats of group II these islets showed almost normal islets with some proliferation and hypertrophy of their beta cells. In conclusion it appears that VS ameliorates diabetes in STZ-induced chronic partially diabetic rats by proliferating the remaining viable beta cells and normalizing the serum insulin level