ABSTRACT
Because statins and ajoene inhibit the 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, we evaluated the hypothesis that the cytotoxic effect of these compounds may be potentiated when both are used in combination on tumor cells. We showed that cotreatment of the murine melanoma B16F10 cell with statins (atorvastatin and pravastatin) and ajoene, all at nontoxic doses, dramatically increased their cytotoxicity. B16F10 cell death induced by statins, but not by ajoene, was prevented by mevalonate and geranylgeranylpyrophosphate. To our knowledge, this is the first report that the combination of statins and ajoene, which alters the mevalonate pathway, might potentiate their cytotoxic effects on tumor cells.
Subject(s)
Disulfides/pharmacology , Heptanoic Acids/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Melanocytes/drug effects , Melanoma, Experimental/pathology , Pravastatin/pharmacology , Pyrroles/pharmacology , Animals , Apoptosis/drug effects , Atorvastatin , Cell Line, Tumor/drug effects , Disulfides/antagonists & inhibitors , Disulfides/pharmacokinetics , Drug Screening Assays, Antitumor , Drug Synergism , Flow Cytometry , Heptanoic Acids/antagonists & inhibitors , Heptanoic Acids/pharmacokinetics , Mevalonic Acid/pharmacology , Mice , Polyisoprenyl Phosphates/pharmacology , Pravastatin/antagonists & inhibitors , Pravastatin/pharmacokinetics , Pyrroles/antagonists & inhibitors , Pyrroles/pharmacokinetics , Sulfoxides , Terpenes/metabolismABSTRACT
Ajoene, (E, Z) -4, 5, 9-trithiadeca-1, 6, 11-triene 9 oxide, is a compound originally isolated from ethanolic extracts of garlic that impairs platelet aggregation by inhibiting the functional exposure of platelet integrins GPIIb/IIIa. In vitro, Ajoene is toxic for several tumoral cell lines, and exert an antiproliferative effect on T. cruzi and murine malaria parasites. Here we show that Ajoene strongly inhibited the proliferation induced in human lymphocytes by the mitogens phytohemagglutinin (PHA), phorbol myristate acetate (PMA) and anti-CD3, and the capping formation induced in B lymphocytes by anti-IgM antibodies. On macrophages, Ajoene was also found to partially inhibit the lypopolysaccharide-induced production of Tumor Necrosis Factor (TNF), and to decrease the phagocytic activity of thioglycolate-elicited mouse peritoneal macrophages for IgG-opsonized, human erythrocytes. Ajoene also partially prevented the lytic effect of human and rabbit TNF on Actinomycin D-treated WEHI 164 cells. These results strongly suggest that Ajoene is a potent modulator of membrane-dependent functions of immune cells.
Subject(s)
Disulfides/pharmacology , Lymphocytes/drug effects , Macrophages, Peritoneal/drug effects , Plant Extracts/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Animals , Cell Division/drug effects , Cell Division/immunology , Cell Survival/drug effects , Cell Survival/immunology , Disulfides/pharmacokinetics , Immunologic Capping/drug effects , Kinetics , Lymphocyte Activation/drug effects , Lymphocytes/cytology , Lymphocytes/immunology , Macrophages, Peritoneal/cytology , Macrophages, Peritoneal/physiology , Mice , Phagocytosis/drug effects , Phagocytosis/immunology , Plant Extracts/pharmacokinetics , Sulfoxides , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Al considerara el grave problema estético y social que constituye la caspa, así como su elevada frecuencia entre la población, se decidió estudiar cuatro principios activos anticaspa, contra placebo. Se consideraron los parámetros clínicos más importantes: número de corneocitos, estudio micológico directo, cultivo, cutirreacción, prurito, irritación del cuero cabelludo y caida del cabello. Los resultados mostraron claramente que el disulfuro de selenio solo y en su presentación con acondicionador, fueron las sustancias más eficaces para combatir el problema
Subject(s)
Humans , Adolescent , Adult , Middle Aged , Male , Female , Dermatitis, Seborrheic/etiology , Dermatitis, Seborrheic/physiopathology , Dermatitis, Seborrheic/therapy , Disulfides/pharmacokinetics , Disulfides/therapeutic use , Selenium/pharmacokinetics , Selenium/therapeutic useABSTRACT
The polymerization of hemoglobin Porto Alegre (HbPA) by inter-tetramer disulfide bond formation at pH 7.6 follows kinetics second order in Hb concnetration. The initial stage of the polymerization was associated with the formation of an HbPAS-S-S-HbPA octamer and a rate constant of 9 x 10***-2M***-1min***-1 was found at 13-C. A later stage of the polymerization wa associated with HbPA-S-S-HbPA-S-S-HbPA dodecamer formation and the rate constant calculated by an approximate treatment was found to be 2.8M***-1 at 13-C. The polymerization by intertetramer disulfide bond formation of HbPA in a 1:1 mixture with HbA follows second orfer kinetics and is monophasic. the lower rate constant found for the HbPA-S-S-HbA octamer (3.9 x 10***-2 M***-1min***-1 at 13-C) is attributed to the formation of S-S bond involving the thiols of the ß9 cysteine from HbPA and the ß93 cysteine from HbA. The 25.6 e.u. more positive "apparent" entropy of activation found for the dodecamer, when comapred to that of the HbPA-S-S-HbPA octamer, is interpreted as due to dehydration of electrically charged groups. The 15.6 e.u. more positive "apparent" entropy of activation of the HbPAS-S-HbA octamer when compared to that of the HbPA-S-S-HbPA octamer is also interpreted as due to dehydration