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BACKGROUND: Yerba mate (YM, Ilex paraguariensis) consumption beneficially affects the bones. However, whether YM components exert their effect on bone cells directly remains elusive. METHODS: We evaluated how main YM components affect osteoblastic (MC3T3-E1) and osteocytic (MLO-Y4) cells in vitro when administered separately or in an aqueous extract. MC3T3-E1 and MLO-Y4 cells were exposed to three different experimental conditions: (1) Caffeine, chlorogenic acid, and their combinations; (2) Caffeine, rutin, and their combinations; (3) Aqueous YM extract. RESULTS: All polyphenol and caffeine concentrations as well as that of their tested combinations significantly increased MC3T3-E1 cell viability from 16.6% to 34.8% compared to the control. In MLO-Y4 cells, the lowest rutin and the two highest caffeine concentrations significantly increased cell viability by 11.9, 14.9, and 13.7%, respectively. While rutin and caffeine combinations tended to increase MLO-Y4 cell viability, different chlorogenic acid and caffeine combinations did not affect it. Finally, the aqueous YM extract significantly increased MLO-Y4, MC3T3-E1, and differentiated MC3T3-E1 cell viability compared to the control without treatment. CONCLUSIONS: YM components (rutin, chlorogenic acid, and caffeine) positively affected bone cells, mainly pre-osteoblast cells. Moreover, the aqueous YM extract significantly increased MLO-Y4, MC3T3-E1, and differentiated MC3T3-E1 cell viabilities indicating an additional relevant nutritional property of YM infusion. Further studies would be required to elucidate the underlying effector mechanism of YM on the bones and its relationship with previously described in vivo positive effects.
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Abstract In recent years, drug repurposing (DR) has gained significant attention as a promising strategy for iden tifying new therapeutic uses of existing drugs. One po tential candidate for DR in cancer treatment is sodium dichloroacetate (DCA), which has been shown to alter tumor metabolism and decrease apoptosis resistance in cancer cells. In this paper, we present a scoping review of the use of DCA for cancer treatment in adult patients, aiming to identify key research gaps in this area. This scoping review aims to explore the existing scientific literature to provide an overview of the use of DCA (any dose, frequency, or route of administration) in adults with cancer. A comprehensive literature search of the medical databases MEDLINE/PubMed, LILACS, EPISTEMONI KOS, the Cochrane Library, and ClinicalTrials was performed. We included publications reporting on adult patients diagnosed with any type of cancer treated with sodium dichloroacetate in combination or not with other drugs. All types of study design were included. A total of 12 articles were included, most of them were case reports. We found a high degree of heteroge neity between them. The most frequent adverse events in the evaluated studies were asthenia, reversible toxic ity, and an increase in liver enzymes. Effectiveness was difficult to evaluate. We conclude that there is insufficient evidence to affirm that treatment with DCA in cancer patients is effective or is safe.
Resumen El reposicionamiento de fármacos (RF) es un enfo que terapéutico reciente que se presenta como una estrategia prometedora para identificar nuevos usos terapéuticos de fármacos existentes. Un candidato potencial para RF en el tratamiento del cáncer es el dicloroacetato de sodio (DCA), el cual ha mostrado la capacidad de alterar el metabolismo tumoral y dismi nuir la resistencia a la apoptosis de células tumorales. La presente es una revisión (scoping review) del uso del DCA para el tratamiento del cáncer en pacientes adultos, que tiene como objetivo identificar brechas de investigación claves en esta área. Esta revisión pretende explorar la literatura científica existente, para propor cionar una visión general del uso del DCA (cualquier dosis, frecuencia o vía de administración) en individuos adultos con cáncer. Se llevó a cabo una búsqueda exhaustiva de la lite ratura en las bases médicas de datos MEDLINE/PubMed, LILACS, EPISTEMONIKOS, the Cochrane Library y Clini calTrials. Se incluyeron publicaciones que informaban sobre pacientes adultos diagnosticados con cualquier tipo de cáncer, tratados con DCA, en combinación o no con otros fármacos. Dichos estudios presentaban distintos tipos de diseño. Se incluyó un total de 12 artículos, la mayoría de los cuales fueron reportes de casos. Se encontró un alto grado de heterogeneidad entre los mismos. Los even tos adversos más frecuentes fueron astenia, toxicidad reversible y aumento de las enzimas hepáticas, siendo la efectividad terapéutica difícil de evaluar. Concluimos que existe evidencia insuficiente para afirmar que el tratamiento con DCA en pacientes con cáncer es efectivo y/o seguro.
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In recent years, drug repurposing (DR) has gained significant attention as a promising strategy for identifying new therapeutic uses of existing drugs. One potential candidate for DR in cancer treatment is sodium dichloroacetate (DCA), which has been shown to alter tumor metabolism and decrease apoptosis resistance in cancer cells. In this paper, we present a scoping review of the use of DCA for cancer treatment in adult patients, aiming to identify key research gaps in this area. This scoping review aims to explore the existing scientific literature to provide an overview of the use of DCA (any dose, frequency, or route of administration) in adults with cancer. A comprehensive literature search of the medical databases MEDLINE/PubMed, LILACS, EPISTEMONIKOS, the Cochrane Library, and ClinicalTrials was performed. We included publications reporting on adult patients diagnosed with any type of cancer treated with sodium dichloroacetate in combination or not with other drugs. All types of study design were included. A total of 12 articles were included, most of them were case reports. We found a high degree of heterogeneity between them. The most frequent adverse events in the evaluated studies were asthenia, reversible toxicity, and an increase in liver enzymes. Effectiveness was difficult to evaluate. We conclude that there is insufficient evidence to affirm that treatment with DCA in cancer patients is effective or is safe.
El reposicionamiento de fármacos (RF) es un enfoque terapéutico reciente que se presenta como una estrategia prometedora para identificar nuevos usos terapéuticos de fármacos existentes. Un candidato potencial para RF en el tratamiento del cáncer es el dicloroacetato de sodio (DCA), el cual ha mostrado la capacidad de alterar el metabolismo tumoral y disminuir la resistencia a la apoptosis de células tumorales. La presente es una revisión (scoping review) del uso del DCA para el tratamiento del cáncer en pacientes adultos, que tiene como objetivo identificar brechas de investigación claves en esta área. Esta revisión pretende explorar la literatura científica existente, para proporcionar una visión general del uso del DCA (cualquier dosis, frecuencia o vía de administración) en individuos adultos con cáncer. Se llevó a cabo una búsqueda exhaustiva de la literatura en las bases médicas de datos MEDLINE/PubMed, LILACS, EPISTEMONIKOS, the Cochrane Library y ClinicalTrials. Se incluyeron publicaciones que informaban sobre pacientes adultos diagnosticados con cualquier tipo de cáncer, tratados con DCA, en combinación o no con otros fármacos. Dichos estudios presentaban distintos tipos de diseño. Se incluyó un total de 12 artículos, la mayoría de los cuales fueron reportes de casos. Se encontró un alto grado de heterogeneidad entre los mismos. Los eventos adversos más frecuentes fueron astenia, toxicidad reversible y aumento de las enzimas hepáticas, siendo la efectividad terapéutica difícil de evaluar. Concluimos que existe evidencia insuficiente para afirmar que el tratamiento con DCA en pacientes con cáncer es efectivo y/o seguro.
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Ácido Dicloroacético , Neoplasias , Humanos , Ácido Dicloroacético/uso terapêutico , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , Reposicionamento de Medicamentos , AdultoRESUMO
AIM: To characterize, by means of univariate and multivariate approaches, the T helper (Th)-1 and Th-2 responses during the different phases of tumor immunoediting. MATERIALS & METHODS: We used a multivariate principal component analysis applied to analyze the joint behavior of serum concentrations of IFN-γ, IL-2, IL-10 and IL-4, during the different phases of tumor immunoediting, in CBi/L mice challenged with M-406 mammary adenocarcinoma. RESULTS & CONCLUSION: Animals in equilibrium phase showed the widest variations in values of the four cytokines. In this experimental model, the role of IFN-γ would be related to tumor growth and progression, while IL-10 would participate in the antitumor immune response.
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Metronomic chemotherapy refers to the minimum biologically effective doses of a chemotherapy agent given as a continuous regimen without extended rest periods. Drug repurposing is defined as the use of an already known drug for a new medical indication, different from the original one. In oncology the combination of these two therapeutic approaches is called "Metronomics". The aim of this work is to evaluate the therapeutic effect of cyclophosphamide in a metronomic schedule in combination with the repurposed drug losartan in two genetically different mice models of triple negative breast cancer. Our findings showed that adding losartan to metronomic cyclophosphamide significantly improved the therapeutic outcome. In both models the combined treatment increased the mice's survival without sings of toxicity. Moreover, we elucidated some of the mechanisms of action involved, which include a decrease of intratumor hypoxia, stimulation of the immune response and remodeling of the tumor microenvironment. The remarkable therapeutic effect, the lack of toxicity, the low cost of the drugs and its oral administration, strongly suggest its translation to the clinical setting in the near future.
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OBJECTIVES: To evaluate the combination of more than one release system in the same formulation as a useful strategy to achieve paclitaxel delivery in a more sustained and controlled manner. METHODS: The present study deals with the preparation of poly(lactide-co-glycolide) microparticles loaded with paclitaxel and included in a chitosan thermo-sensitive gelling solution. The microparticles were characterized by their size, shape and drug loading. The formulation was characterized by scanning electron microscopy, in vitro release experiments and was evaluated in mice bearing mammary adenocarcinoma. KEY FINDINGS: The formation of paclitaxel crystals in a pharmaceutical formulation reduces its efficacy. In this work, the use of microparticles avoided this phenomenon. Combining more than one delivery system allowed delivering paclitaxel in a more sustained and controlled manner leading to a long-term effect in the site of action. The formulation showed an inhibition in tumour volume of 63.0% in comparison with the control group. CONCLUSIONS: One intratumour injection of gelling solution containing the microparticles was at least as efficacious as four intraperitoneal injections of a commercial formulation. In addition, the delivery system was nontoxic, and the treated mice presented the highest percentage of tumour regression and median survival time.
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Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Quitosana/química , Portadores de Fármacos , Neoplasias Mamárias Animais/tratamento farmacológico , Paclitaxel/farmacologia , Poliglactina 910/química , Temperatura , Adenocarcinoma/patologia , Animais , Antineoplásicos Fitogênicos/química , Química Farmacêutica/métodos , Preparações de Ação Retardada , Composição de Medicamentos , Liberação Controlada de Fármacos , Feminino , Géis , Cinética , Neoplasias Mamárias Animais/patologia , Camundongos Endogâmicos BALB C , Paclitaxel/química , Tamanho da Partícula , Carga Tumoral/efeitos dos fármacosRESUMO
Identifying tumor biomarkers associated with clinical behavior in breast cancer patients may allow higher accuracy in the selection of treatment. Different types of cells were determined in the primary tumors of stage I, II, and III of breast cancer patients, who were assigned to one of the two groups: (1) disease-free or (2) relapsed/progressed, at 5 years after primary treatment. We studied 32 tumor samples. CD4+ lymphocytes and CD44+CD24-/low cells (cancer stem cells) showed a significant association with clinical outcome at 5 years of primary treatment, while CD8+, Foxp3+, CD34+, and myeloid-derived suppressor cells did not show any association. Coincident with the results of individual analysis, we identified CD4+ cells and CD44+CD24-/low cells as good predictors of long-term clinical outcome in a logistic regression.
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Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Células-Tronco Neoplásicas/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Células-Tronco Neoplásicas/patologia , Projetos PilotoRESUMO
Discovery of new drugs for cancer treatment is an expensive and time-consuming process and the percentage of drugs reaching the clinic remains quite low.Drug repositioning refers to the identification and development of new uses for existing drugs and represents an alternative drug development strategy.In this work, we evaluated the antitumor effect of metronomic treatment with a combination of two repositioned drugs, metformin and propranolol, in triple negative breast cancer models.By in vitro studies with five different breast cancer derived cells, we observed that combined treatment decreased proliferation (P < 0.001), mitochondrial activity (P < 0.001), migration (P < 0.001) and invasion (P < 0.001). In vivo studies in immunocompetent mice confirmed the potential of this combination in reducing tumor growth (P < 0.001) and preventing metastasis (P < 0.05).Taken together our results suggest that metformin plus propranolol combined treatment might be beneficial for triple negative breast cancer control, with no symptoms of toxicity.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Metformina/farmacologia , Propranolol/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Sinergismo Farmacológico , Metabolismo Energético , Feminino , Glicólise , Humanos , Hipoglicemiantes/farmacologia , Concentração Inibidora 50 , Camundongos , Biogênese de Organelas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Following previous metronomic meetings in Marseille (2011), Milano (2014), and Mumbai (2016), the first Latin American metronomic meeting was held in the School of Medical Sciences, National University of Rosario, Rosario, Argentina on 27 and 28 of May, 2016. For the first time, clinicians and researchers with experience in the field of metronomics, coming from different countries in Latin America, had the opportunity of presenting and discussing their work. The talks were organised in three main sessions related to experience in the pre-clinical, and clinical (paediatric and adult) areas. The different presentations demonstrated that the fields of metronomic chemotherapy and repurposing drugs in oncology, known as metronomics, constitute a branch of cancer therapy in permanent evolution, which have strong groups working in Latin America, both in the preclinical and the clinical settings including large, adequately designed randomised studies. It was shown that metronomics offers treatments, which, whether they are combined or not with the standard therapeutic approaches, are not only effective but also minimally toxic, with the consequent improvement of the patient's quality of life, and inexpensive, a feature very important in low resource clinical settings. The potential use of metronomic chemotherapy was proposed as a cost/effective treatment in low-/middle-income countries, for adjuvant therapy in selected tumours. The fundamental role of the governmental agencies and non-governmental alliances, as the Metronomic Global Health Initiative, in supporting this research with public interest was underlined.
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AIM: The objective of the study was to detect changes in quality of life (QoL) in metastatic breast cancer patients treated with metronomic chemotherapy with daily low doses of cyclophosphamide and celecoxib. MATERIAL & METHODS: Patients included in a Phase II trial, treated with metronomic cyclophosphamide and celecoxib were included in the QoL study. Assessment of QoL was carried out every 2 months by the Functional Assessment of Cancer Therapy Breast (FACT-B) questionnaire, Brief Pain Inventory and Eastern Cooperative Oncologic Group scale. Data were analyzed at three time points: baseline (BL); middle of treatment (MT); and end of treatment (ET). RESULTS: A total of 20 patients were included. All patients were heavily pretreated. Treatment showed a good and safe therapeutic profile. With FACT-B questionnaire, no significant differences were observed during the response period (BL-MT). However, a significant increase was observed in the Emotional well-being and Additional concerns axes, when the last time point was included in the analysis (BL-MT-ET). A significant decrease in the proportion of patients with pain was found when comparing BL with ET (p = 0.046). The assessment with Eastern Cooperative Oncologic Group scale showed that 26.7% (4/15) of the patients improved their functional status and 40% (6/15) showed no changes, while 33.3% (5/10) worsened it. CONCLUSION: Patients treated metronomically for several months did not worsen their QoL. A high proportion of patients showed improvement or no changes and there were less patients with pain at the end of the treatment.