RESUMEN
Benznidazole is the first-line drug used in treating Chagas disease, which is caused by the parasite Trypanosoma cruzi (T. cruzi). However, benznidazole has limited efficacy and several adverse reactions. Pentamidine is an antiprotozoal drug used in the treatment of leishmaniasis and African trypanosomiasis. In T. cruzi, pentamidine blocks the transport of putrescine, a precursor of trypanothione, which constitutes an essential molecule in the resistance of T. cruzi to benznidazole. In the present study, we describe the effect of the combination of benznidazole and pentamidine on isolated parasites, mammalian cells and in mice infected with T. cruzi. In isolated trypomastigotes, we performed a dose-matrix scheme of combinations, where pentamidine antagonized the effect of benznidazole, mainly at concentrations below the EC50 of pentamidine. In T. cruzi-infected mammalian cells, pentamidine reversed the effect of benznidazole (measured by qPCR). In comparison, in infected BALB/c mice, pentamidine failed to get synergy with benznidazole, measured on mice survival, parasitemia and amastigote nest quantification. To further explain the in vitro antagonism, we explored whether pentamidine affects intracellular trypanothione levels, however, pentamidine produced no change in trypanothione concentrations. Finally, the T. cruzi polyamine permease (TcPAT12) was overexpressed in epimastigotes, showing that pentamidine has the same trypanocidal effect, independently of transporter expression levels. These results suggest that, in spite of the high potency in the putrescine transport blockade, TcPAT12 permease is not the main target of pentamidine, and could explain the lack of synergism between pentamidine and benznidazole.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Nitroimidazoles/antagonistas & inhibidores , Pentamidina/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Enfermedad de Chagas/patología , Chlorocebus aethiops , ADN Protozoario/análisis , ADN Protozoario/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Glutatión/análogos & derivados , Glutatión/efectos de los fármacos , Glutatión/metabolismo , Macrófagos/parasitología , Masculino , Ratones , Ratones Endogámicos BALB C , Miocardio/patología , Parasitemia/tratamiento farmacológico , Parasitemia/parasitología , Putrescina/metabolismo , Distribución Aleatoria , Espermidina/análogos & derivados , Espermidina/metabolismo , Timidina/metabolismo , Tripanocidas/antagonistas & inhibidores , Células VeroRESUMEN
Tumor cells principally exhibit increased mitochondrial transmembrane potential (ΔΨ(m)) and altered metabolic pathways. The therapeutic targeting and delivery of anticancer drugs to the mitochondria might improve treatment efficacy. Gallic acid exhibits a variety of biological activities, and its ester derivatives can induce mitochondrial dysfunction. Four alkyl gallate triphenylphosphonium lipophilic cations were synthesized, each differing in the size of the linker chain at the cationic moiety. These derivatives were selectively cytotoxic toward tumor cells. The better compound (TPP(+)C10) contained 10 carbon atoms within the linker chain and exhibited an IC50 value of approximately 0.4-1.6 µM for tumor cells and a selectivity index of approximately 17-fold for tumor compared with normal cells. Consequently, its antiproliferative effect was also assessed in vivo. The oxygen consumption rate and NAD(P)H oxidation levels increased in the tumor cell lines (uncoupling effect), resulting in a ΔΨ(m) decrease and a consequent decrease in intracellular ATP levels. Moreover, TPP(+)C10 significantly inhibited the growth of TA3/Ha tumors in mice. According to these results, the antineoplastic activity and safety of TPP(+)C10 warrant further comprehensive evaluation.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Ácido Gálico/análogos & derivados , Ácido Gálico/síntesis química , Adenosina Trifosfato/metabolismo , Análisis de Varianza , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/efectos de los fármacos , Inhibidores de Caspasas/síntesis química , Inhibidores de Caspasas/farmacología , Cationes/química , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ácido Gálico/farmacología , Humanos , L-Lactato Deshidrogenasa/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Dilatación Mitocondrial/efectos de los fármacos , NADP/metabolismo , Oxidación-Reducción , Consumo de Oxígeno/efectos de los fármacos , Reproducibilidad de los Resultados , Desacopladores/síntesis química , Desacopladores/farmacologíaRESUMEN
The extracts of several plants of Central Chile exhibited anti-Trypanosoma cruzi trypomastigotes activity. Most active extracts were those obtained from Podanthus ovatifolius, Berberis microphylla, Kageneckia oblonga, and Drimys winteri. The active extract of Drimys winteri (IC50 51.2 microg/mL) was purified and three drimane sesquiterpenes were obtained: polygodial, drimenol, and isodrimenin. Isodrimenin and drimenol were found to be active against the trypomastigote form of T. cruzi with IC50 values of 27.9 and 25.1 microM, respectively.
Asunto(s)
Antiprotozoarios/farmacología , Extractos Vegetales/farmacología , Plantas Medicinales/química , Trypanosoma cruzi/efectos de los fármacos , Animales , Chile , Chlorocebus aethiops , Cromatografía en Capa Delgada , Espectroscopía de Resonancia Magnética , Células VeroRESUMEN
Changes in mitochondrial ATP synthesis can affect the function of tumor cells due to the dependence of the first step of glycolysis on mitochondrial ATP. The oxidative phosphorylation (OXPHOS) system is responsible for the synthesis of approximately 90% of the ATP in normal cells and up to 50% in most glycolytic cancers; therefore, inhibition of the electron transport chain (ETC) emerges as an attractive therapeutic target. We studied the effect of a lipophilic isoprenylated catechol, 3-hydroxybakuchiol (3-OHbk), a putative ETC inhibitor isolated from Psoralea glandulosa. 3-OHbk exerted cytotoxic and anti-proliferative effects on the TA3/Ha mouse mammary adenocarcinoma cell line and induced a decrease in the mitochondrial transmembrane potential, the activation of caspase-3, the opening of the mitochondrial permeability transport pore (MPTP) and nuclear DNA fragmentation. Additionally, 3-OHbk inhibited oxygen consumption, an effect that was completely reversed by succinate (an electron donor for Complex II) and duroquinol (electron donor for Complex III), suggesting that 3-OHbk disrupted the electron flow at the level of Complex I. The inhibition of OXPHOS did not increase the level of reactive oxygen species (ROS) but caused a large decrease in the intracellular ATP level. ETC inhibitors have been shown to induce cell death through necrosis and apoptosis by increasing ROS generation. Nevertheless, we demonstrated that 3-OHbk inhibited the ETC and induced apoptosis through an interaction with Complex I. By delivering electrons directly to Complex III with duroquinol, cell death was almost completely abrogated. These results suggest that 3-OHbk has antitumor activity resulting from interactions with the ETC, a system that is already deficient in cancer cells.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Catecoles/farmacología , Transporte de Electrón/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Fenoles/farmacología , Animales , Antineoplásicos Fitogénicos/química , Catecoles/química , Técnicas de Cultivo de Célula , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/metabolismo , Mitocondrias/patología , Dilatación Mitocondrial/efectos de los fármacos , Estructura Molecular , Necrosis , Fenoles/química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Chronic Chagas' disease affects 10-30 % of patients infected with Trypanosoma cruzi, and it mainly manifests as cardiomyopathy. Important pathophysiological mechanisms involved in the cardiac lesions include activation of the endothelium and induced microvascular alterations. These processes involve the production of endothelial adhesion molecules and thromboxane A2, which are involved in inflammatory cell recruitment and platelet aggregation, respectively. Cyclooxygenase inhibitors such as aspirin decrease thromboxane production and alter the course of Chagas' disease, both in the acute and chronic phases. We studied the effects of the administration of low and high doses of aspirin during the early phase of T. cruzi infection, following microvascular damage in the context of a chronic murine model of Chagas' disease. The effects of both schedules were assessed at 24 and 90 days postinfection by evaluating parasitemia, mortality, and cardiac histopathological changes as well as the expression of ICAM, VCAM, and E-selectin in cardiac tissue. Thromboxane A2, soluble ICAM, and E-selectin blood levels were also measured. While aspirin did not affect parasitemia or mortality in the infected mice, it decreased both cardiac inflammatory infiltrates and thromboxane levels. Additionally, at 90 days postinfection, aspirin normalized sICAM and sE-selectin levels. Considering the improved endothelial function induced by aspirin, we propose the possibility of including this drug in clinical therapy to treat chronic Chagas' disease.
Asunto(s)
Antiinflamatorios/uso terapéutico , Aspirina/uso terapéutico , Cardiomiopatía Chagásica/tratamiento farmacológico , Cardiomiopatía Chagásica/prevención & control , Endotelio Vascular/patología , Animales , Cardiomiopatía Chagásica/patología , Enfermedad Crónica , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/uso terapéutico , Masculino , Ratones , Ratones Endogámicos BALB C , Parasitemia/tratamiento farmacológico , Análisis de Supervivencia , Tromboxano A2/sangreRESUMEN
Chagas' disease, produced by Trypanosoma cruzi, affects more than 8 million people, producing approximately 10,000 deaths each year in Latin America. Migration of people from endemic regions to developed countries has expanded the risk of infection, transforming this disease into a globally emerging problem. PGE2 and other eicosanoids contribute to cardiac functional deficits after infection with T. cruzi. Thus, the inhibition of host cyclooxygenase (COX) enzyme emerges as a potential therapeutic target. In vivo studies about the effect of acetylsalicylic acid (ASA) upon T. cruzi infection are controversial, and always report the effect of ASA at a single dose. Therefore, we aimed to analyze the effect of ASA at different doses in an in vivo model of infection and correlate it with the production of arachidonic acid metabolites. ASA decreased mortality, parasitemia, and heart damage in T. cruzi (Dm28c) infected mice, at the low doses of 25 and 50 mg/Kg. However, this effect disappeared when the high ASA doses of 75 and 100 mg/Kg were used. We explored whether this observation was related to the metabolic shift toward the production of 5-lipoxygenase derivatives, and although we did not observe an increase in LTB4 production in infected RAW cells and mice infected, we did find an increase in 15-epi-LXA4 (an ASA-triggered lipoxin). We also found high levels of 15-epi-LXA4 in T. cruzi infected mice treated with the low doses of ASA, while the high ASA doses decreased 15-epi-LXA4 levels. Importantly, 15-epi-LXA4 prevented parasitemia, mortality, and cardiac changes in vivo and restored the protective role in the treatment with a high dose of ASA. This is the first report showing the production of ASA-triggered lipoxins in T. cruzi infected mice, which demonstrates the role of this lipid as an anti-inflammatory molecule in the acute phase of the disease.
Asunto(s)
Aspirina/uso terapéutico , Enfermedad de Chagas/prevención & control , Lipoxinas/metabolismo , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/patogenicidad , Animales , Línea Celular , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
In Latin America, there are about 10-12 million people infected with Trypanosoma cruzi, the agent of Chagas' disease, one of the most important neglected tropical parasitism. Identification of molecular targets, specific for the aggressor or host cells or both, may be useful in the development of pharmacological and/or immunological therapeutic tools. Classic efforts in Chagas' disease explore those strategies. Although the immune system frequently controls parasite aggressions, sterile immunity is seldom achieved and chronic interactions are thus established. However, laboratory-modified immunologic probes aimed at selected parasite targets, may be more effective than their unmodified counterparts. Calreticulin (CRT) from vertebrates is a calcium binding protein, present mainly in the endoplasmic reticulum (ER), where it directs the conformation of proteins and controls calcium levels. We have isolated, gene-cloned, expressed and characterized T. cruzi calreticulin (TcCRT). Upon infection, the parasite can translocate this molecule from the ER to the surface, where it inhibits both the classical and lectin complement pathways. Moreover, by virtue of its capacity to bind and inactivate first complement component C1, it promotes parasite infectivity. These two related properties reside in the central domain of this molecule. A different domain, amino terminal, binds to endothelial cells, thus inhibiting their angiogenic capacity. Since tumor growth depends, to a large extent on angiogenesis, their growth is also inhibited.
Asunto(s)
Calreticulina/metabolismo , Enfermedad de Chagas/inmunología , Enfermedad de Chagas/parasitología , Interacciones Huésped-Parásitos , Neoplasias/patología , Trypanosoma cruzi/fisiología , Inhibidores de la Angiogénesis , Animales , Proliferación Celular , Enfermedad de Chagas/patología , Humanos , Neoplasias/metabolismo , Trypanosoma cruzi/inmunología , Trypanosoma cruzi/patogenicidadRESUMEN
Chagas disease is one of the most important endemic diseases in Latin America, caused by Trypanosoma cruzi. The drugs used for the treatment of this disease, nifurtimox and benznidazole, are toxic and present severe side effects. The need of effective drugs, without adverse effects, has stimulated the search for new compounds with potential clinical utility. An overview of a number of natural naphthoquinones tested against T. cruzi parasites is provided. Among natural naphthoquinones, lapachol, ß-lapachone and its α-isomer have demonstrated useful trypanocidal activities. In the search for new trypanocidal agents, this review outlines different structural modifications of natural quinones, as well as synthetic quinones, which have been subjected to trypanocidal studies. This review summarizes the mechanism of action and structure-activity relationships of the quinone derivatives, including some theoretical calculations that discuss the correlation of stereo electronic properties with the trypanocidal activity. In this context, this review will be useful for the development of new antichagasic drugs based mainly on structural modification of natural quinones.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Naftoquinonas/química , Tripanocidas/química , Trypanosoma cruzi/efectos de los fármacos , Humanos , Naftoquinonas/síntesis química , Naftoquinonas/uso terapéutico , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/uso terapéuticoRESUMEN
Nifurtimox and benznidazole are the only active drugs against Trypanosoma cruzi; however, they have limited efficacy and severe side effects. During primoinfection, T. cruzi infected macrophages mount an antiparasitic response, which the parasite evades through an increase of tumor growth factor beta and PGE(2) activation as well as decreased iNOS activity. Thus, prostaglandin synthesis inhibition with aspirin might increase macrophage antiparasitic activity and increase nifurtimox and benznidazole effect. Aspirin alone demonstrated a low effect upon macrophage antiparasitic activity. However, isobolographic analysis of the combined effects of aspirin, nifurtimox and benznidazole indicated a synergistic effect on T. cruzi infection of RAW cells, with combinatory indexes of 0.71 and 0.61, respectively. The observed effect of aspirin upon T. cruzi infection was not related with the PGE(2) synthesis inhibition. Nevertheless, NO() levels were restored by aspirin in T. cruzi-infected RAW cells, contributing to macrophage antiparasitic activity improvement. Thus, the synergy of aspirin with nifurtimox and benznidazole is due to the capability of aspirin to increase antiparasitic activity of macrophages.
Asunto(s)
Aspirina/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Nifurtimox/farmacología , Nitroimidazoles/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Concentración 50 Inhibidora , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/parasitología , Ratones , Óxido Nítrico/metabolismoRESUMEN
There are approximately 7.8 million people in Latin America, including Chile, who suffer from Chagas disease and another 28 million who are at risk of contracting it. Chagas is caused by the flagellate protozoan Trypanosoma cruzi. It is a chronic disease, where 20%-30% of infected individuals develop severe cardiopathy, with heart failure and potentially fatal arrhythmias. Currently, Chagas disease treatment is more effective in the acute phase, but does not always produce complete parasite eradication during indeterminate and chronic phases. At present, only nifurtimox or benznidazole have been proven to be superior to new drugs being tested. Therefore, it is necessary to find alternative approaches to treatment of chronic Chagas. The current treatment may be rendered more effective by increasing the activity of anti-Chagasic drugs or by modifying the host's immune response. We have previously shown that glutathione synthesis inhibition increases nifurtimox and benznidazole activity. In addition, there is increasing evidence that cyclooxygenase inhibitors present an important effect on T. cruzi infection. Therefore, we found that aspirin reduced the intracellular infection in RAW 264.7 cells and, decreased myocarditis extension and mortality rates in mice. However, the long-term benefit of prostaglandin inhibition for Chagasic patients is still unknown.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Tripanocidas/uso terapéutico , Trypanosoma cruzi/patogenicidad , Enfermedad Aguda , Animales , Cardiomiopatía Chagásica/tratamiento farmacológico , Cardiomiopatía Chagásica/inmunología , Cardiomiopatía Chagásica/parasitología , Enfermedad de Chagas/inmunología , Enfermedad de Chagas/parasitología , Enfermedad Crónica , Ciclooxigenasa 1/fisiología , Ciclooxigenasa 2/fisiología , Humanos , Ratones , Nifurtimox/uso terapéutico , Nitroimidazoles/uso terapéutico , Trypanosoma cruzi/inmunologíaRESUMEN
There are approximately 7.8 million people in Latin America, including Chile, who suffer from Chagas disease and another 28 million who are at risk of contracting it. Chagas is caused by the flagellate protozoan Trypanosoma cruzi. It is a chronic disease, where 20 percent-30 percent of infected individuals develop severe cardiopathy, with heart failure and potentially fatal arrhythmias. Currently, Chagas disease treatment is more effective in the acute phase, but does not always produce complete parasite eradication during indeterminate and chronic phases. At present, only nifurtimox or benznidazole have been proven to be superior to new drugs being tested. Therefore, it is necessary to find alternative approaches to treatment of chronic Chagas. The current treatment may be rendered more effective by increasing the activity of anti-Chagasic drugs or by modifying the host's immune response. We have previously shown that glutathione synthesis inhibition increases nifurtimox and benznidazole activity. In addition, there is increasing evidence that cyclooxygenase inhibitors present an important effect on T. cruzi infection. Therefore, we found that aspirin reduced the intracellular infection in RAW 264.7 cells and, decreased myocarditis extension and mortality rates in mice. However, the long-term benefit of prostaglandin inhibition for Chagasic patients is still unknown.
Asunto(s)
Animales , Humanos , Ratones , Enfermedad de Chagas/tratamiento farmacológico , Tripanocidas/uso terapéutico , Trypanosoma cruzi/patogenicidad , Enfermedad Aguda , Enfermedad Crónica , Cardiomiopatía Chagásica/tratamiento farmacológico , Cardiomiopatía Chagásica/inmunología , Cardiomiopatía Chagásica/parasitología , Enfermedad de Chagas/inmunología , Enfermedad de Chagas/parasitología , Ciclooxigenasa 1/fisiología , /fisiología , Nifurtimox/uso terapéutico , Nitroimidazoles/uso terapéutico , Trypanosoma cruzi/inmunologíaRESUMEN
BACKGROUND: Multidrug resistance (MDR) continues being the major obstacle for successful anticancer chemotherapy. MATERIALS AND METHODS: The action of nordihydroguaiaretic acid (NDGA) and its tetra-acetylated derivative (NDGATA) on TA3 mouse mammary adenocarcinoma cells and their ability to restore doxorubicin (DOX), cisplatin (CPT) and methotrexate (MTX) sensitivity of the multiresistant variant TA3-MTX-R was examined. RESULTS: Both NDGA and NDGATA synergistically enhanced the cytotoxicity of DOX, CPT and MTX, with a more evident effect in the TA3-MTX-R than in the TA3 cells. NDGATA was more effective than NDGA, as analyzed by the isobologram method. The combination of NDGATA and DOX also reduced the tumor growth rate in mice. Although it did not prolong the median survival time, 30% of mice showed no vestiges of tumor 200 days after implantation with either TA3 or TA3-MTX-R cells. Moreover, NDGA and NDGATA increased the accumulation of DOX and rhodamine (RHO) 123 in both cell lines. CONCLUSION: NDGA and NDGATA are able to chemosensitize tumor cells and combination therapy with NDGATA and DOX is effective at inhibiting tumor growth in mice.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Mamarias Animales/tratamiento farmacológico , Masoprocol/farmacología , Acetilación , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Antineoplásicos/química , Línea Celular Tumoral , Cisplatino/farmacología , Doxorrubicina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Femenino , Longevidad/efectos de los fármacos , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Masoprocol/química , Metotrexato/farmacología , Ratones , Rodamina 123/metabolismoRESUMEN
Eight new platinum(II) complexes with 3-(5-nitrofuryl)acroleine thiosemicarbazones showing anti-trypanosomal activity were synthesized, characterized and in vitro evaluated. Most of the complexes showed IC(50) values in the micromolar range against two different strains of Trypanosoma cruzi, causative agent of Chagas disease (American Trypanosomiasis). In addition, most of the newly developed complexes, together with the analogous platinum 5-nitrofuraldehyde containing thiosemicarbazones previously reported, resulted more active than the reference trypanocidal drug nifurtimox on the infective trypomastigote form of the parasite. Their capacity to produce free radicals that could lead to parasite death was evaluated by ESR experiments in the parasite and by respiration measurements. Compounds were tested for their DNA interaction ability. Results showed that some of the compounds could act as dual inhibitors in the parasite, through production of toxic free radicals and interaction with DNA. All the results were compared with those previously reported for the free ligands, the analogous palladium(II) compounds and the previously reported series of platinum(II) compounds.
Asunto(s)
Compuestos Organoplatinos/farmacología , Tiosemicarbazonas/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , ADN/efectos de los fármacos , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/química , Tripanocidas/síntesis química , Tripanocidas/químicaRESUMEN
This work presents the development of analytical methodologies by UV spectrophotometry and HPLC to characterize five nitroarylbenzimidazole derivatives with activity against Trypanosoma cruzi: NB, BNB, PNB, PMNB and PCNB. Both methodologies exhibit adequate repeatabilities and reproducibilities (CV<2%) and recoveries higher than 98%. The ionization constants (pK(a)), lipophilicity (log P) and effective permeability (Pe) are reported. The five compounds present an inhibitory effect on the T. cruzi growth (epimastigotes) at 1-100 microM concentration range in an order rank of PMNB>PCNB>PNB>BNB>NB. Additionally, cyclic voltammetric data reveal that the nitroarylbenzimidazole derivatives might sustain their effects on growth and oxygen uptake on T. cruzi epimastigotes.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Tripanocidas/síntesis química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Bencimidazoles/química , Electroquímica , Cinética , Espectrofotometría Ultravioleta , Tripanocidas/químicaRESUMEN
The effects of nordihydroguaiaretic acid (NDGA) and its tetraacetylated derivative (NDGATA) on the growth, oxygen consumption, adenosine 5'-triphosphate (ATP) level and viability of mouse mammary adenocarcinoma TA3 and its multiresistant variant TA3-MTX-R cell lines were determined. NDGA inhibited mitochondrial carbonyl cyanide m-chlorophenylhydrazone (CCCP)-stimulated oxygen consumption in mouse liver and tumor cells when glutamate plus malate or succinate was added as substrate. The effects were considerably weaker when respiration was supported by duroquinol, indicating that NDGA inhibited primarily mitochondrial electron flow located at some point before ubiquinone. Although NDGATA only inhibited the electron flow through complex I, it was more efficient and selective than NDGA because mouse liver mitochondria were significantly less sensitive to it than both tumor cell lines tested. NDGA and NDGATA inhibited mitochondrial ATP synthesis and, consequently, cell viability and growth rate were also decreased. NDGA and NDGATA inhibited the growth of intramuscularly implanted tumor cells, indicating that NDGATA was also antineoplastic in vivo. In conclusion, NDGATA is cytotoxic to tumor cells, provoking selective induction of mitochondrial dysfunctions, which could be interesting as potential antitumoral agent.
Asunto(s)
Adenocarcinoma/patología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Masoprocol/química , Masoprocol/farmacología , Acetilación , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Respiración de la Célula/efectos de los fármacos , Masoprocol/uso terapéutico , Ratones , Mitocondrias Hepáticas/efectos de los fármacos , Trasplante de Neoplasias , Oxígeno/metabolismo , Tasa de SupervivenciaRESUMEN
L-buthionine (S,R)-sulfoximine (BSO) at a dose of 220 mg/kg of body weight/day showed an anti-Trypanosoma cruzi effect in infected mice, increasing their survival rate and decreasing the parasitemias and parasite burden in the hearts. Treatment with BSO plus nifurtimox caused an increase in the survival rate in comparison to the rates with treatment with each drug alone.
Asunto(s)
Butionina Sulfoximina/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Nifurtimox/farmacología , Trypanosoma cruzi/efectos de los fármacos , Enfermedad Aguda , Animales , Butionina Sulfoximina/uso terapéutico , Enfermedad de Chagas/mortalidad , Enfermedad de Chagas/parasitología , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Ratones , Ratones Endogámicos BALB C , Nifurtimox/uso terapéutico , Tasa de Supervivencia , Tripanocidas/farmacologíaRESUMEN
In the search for new therapeutic tools against Chagas' disease (American Trypanosomiasis) two series of new platinum(II) complexes with bioactive 5-nitrofuryl containing thiosemicarbazones as ligands were synthesized, characterized and in vitro evaluated. Most of the complexes showed IC50 values in the muM range against two different strains of Trypanosoma cruzi, causative agent of the disease, being as active as the anti-trypanosomal drug Nifurtimox. In particular, the coordination of L3 (4-ethyl-1-(5-nitrofurfurylidene)thiosemicarbazide) to Pt(II) forming [Pt(L3)2] lead to almost a five-fold activity increase in respect to the free ligand. Trying to get an insight into the trypanocidal mechanism of action of these compounds, DNA and redox metabolism (intra-parasite free radical production) were evaluated as potential parasite targets. Results suggest that the complexes could inhibit parasite growth through a dual mechanism of action involving production of toxic free radicals by bioreduction and DNA interaction.
Asunto(s)
Compuestos Organoplatinos/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , ADN/química , Radicales Libres/metabolismo , Resonancia Magnética Nuclear Biomolecular , Compuestos Organoplatinos/síntesis química , Espectrofotometría Infrarroja , Espectrometría Raman , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/farmacología , Tripanocidas/síntesis químicaRESUMEN
Derivatives of natural quinones with biological activities, such as lapachol, alpha- and beta-lapachones, have been synthesized and their trypanocidal activity evaluated in vitro in Trypanosoma cruzi cells. All tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity as compared with current trypanocidal drugs, nifurtimox and benznidazole. The results presented here show that the anti-T. cruzi activity of the alpha-lapachone derivatives can be increased by the replacement of the benzene ring by a pyridine moiety. Free radical production and consequently oxidative stress through redox cycling or production of electrophilic metabolites are the potential biological mechanism of action for these synthetic quinones.
Asunto(s)
Naftoquinonas/síntesis química , Naftoquinonas/farmacología , Tripanocidas/síntesis química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Estructura Molecular , Naftoquinonas/química , Oxidación-Reducción , Estereoisomerismo , Tripanocidas/químicaRESUMEN
Alkyl esters of gallic acid inhibited the respiration rate of mouse sarcoma 786A and mouse mammary adenocarcinoma TA3 cell lines and its multiresistant variant TA3-MTX-R more effectively than gallic acid, both in the absence and in the presence of the uncoupler CCCP. The order of inhibition of the respiration rate by gallates in intact cells was n-octyl- approximately iso-amyl- approximately n-amyl- approximately iso-butyl->n-butyl->iso-propyl->n-propyl-gallate>>gallic acid. Sarcoma 786A was significantly more susceptible to all seven esters than the TA3 cell line. Respiration rates of the TA3-MTX-R cell line showed almost the same sensitivity to these esters as the TA3 cell line. However, hepatocytes were significantly less sensitive than all tumor cells tested. These alkyl gallates blocked mitochondrial electron flow, mainly at the NADH-CoQ segment, preventing ATP synthesis, which would lead to cellular death. These esters also inhibited, in the same order of potencies as respiration, the growth of 786A, TA3 and TA3-MTX-R cells in culture. In mice carrying TA3 or TA3-MTX-R tumor cells, an important decrease of the tumor growth rate and an increase of survival were observed when mice were treated with iso-butyl gallate alone or in combination with doxorubicin. These results indicate that alkyl gallates are selectively cytotoxic to tumor cells, which may be due to the mitochondrial dysfunctions of these cells.
Asunto(s)
Antineoplásicos/farmacología , Hepatocitos/efectos de los fármacos , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Respiración de la Célula/efectos de los fármacos , Células Cultivadas , Ensayos de Selección de Medicamentos Antitumorales , Transporte de Electrón , Ácido Gálico/análogos & derivados , Ácido Gálico/farmacología , Ratones , Mitocondrias Hepáticas/efectos de los fármacos , Mitocondrias Hepáticas/metabolismo , Galato de Propilo/farmacología , Ratas , Pruebas de ToxicidadRESUMEN
Current knowledge of the biochemistry of Trypanosoma cruzi has led to the development of new drugs and the understanding of their mode of action. Some trypanocidal drugs such as nifurtimox and benznidazole act through free radical generation during their metabolism. T. cruzi is very susceptible to the cell damage induced by these metabolites because enzymes scavenging free radicals are absent or have very low activities in the parasite. Another potential target is the biosynthetic pathway of glutathione and trypanothione, the low molecular weight thiol found exclusively in trypanosomatids. These thiols scavenge free radicals and participate in the conjugation and detoxication of numerous drugs. Inhibition of this key pathway could render the parasite much more susceptible to the toxic action of drugs such as nifurtimox and benznidazole without affecting the host significantly. Other drugs such as allopurinol and purine analogs inhibit purine transport in T. cruzi, which cannot synthesize purines de novo. Nitroimidazole derivatives such as itraconazole inhibit sterol metabolism. The parasite's respiratory chain is another potential therapeutic target because of its many differences with the host enzyme complexes. The pharmacological modulation of the host's immune response against T. cruzi infection as a possible chemotherapeutic target is discussed. A large set of chemicals of plant origin and a few animal metabolites active against T. cruzi are enumerated and their likely modes of action are briefly discussed.