RESUMEN
Citrate, a major component of processed foods, appears as either preservative or flavor enhancer. With no concentration limit, citrate is consumed in large quantities worldwide, principally in ultra-processed foods (UPF). UPF are encountered in Western diets (rich in saturated fat and sucrose), where consumption is directly associated with many conditions, such as obesity and diabetes, among others. Here, we administered a High-Fat, High-Sucrose (HFHS) diet to mice, enriched or not with citrate (67 mg g-1 diet), aimed to simulate UPF citrate consumption. Our results showed that citrate enrichment prevented the HFHS-induced lipid deposition in the liver and adipose tissues of the animals. Moreover, the treatment induced mitochondrial biogenesis in white adipose tissues, via upregulation of PCG1α. As a result, citrate enhancement upregulated UCP1, suggesting the browning of white adipose tissues. Nevertheless, the citrate-enhanced diet did not prevent HFHS-induced insulin resistance and causes further liver inflammation and injury. Altogether, our results clearly showed that, associated to UPF consumption, the excess of dietary citrate has caused harmful effects being associated to non-obesity related liver inflammatory diseases and insulin resistance.
Asunto(s)
Resistencia a la Insulina , Animales , Ratones , Ácido Cítrico , Dieta Alta en Grasa , Dieta Occidental , Resistencia a la Insulina/fisiología , Ratones Endogámicos C57BL , Obesidad/etiología , Sacarosa , Aumento de PesoRESUMEN
The immune system is a key component of tumorigenesis, with the latter promoting the development of cancer, its progression and metastasis. In fact, abundant infiltration of tumor-associated macrophages (TAM), which are M2-like macrophages, has been associated with a poor outcome in most types of cancers. Here, we show that lactate produced by murine melanoma B16F10 cells induces an M2-like profile in cultured macrophages. Further, we demonstrate that clotrimazole (CTZ), an off-target anti-tumor drug, abolishes lactate effects on the activation of macrophages and induces the expression of M1-like markers. We show that clotrimazole has cytotoxic effects on tumor cells by negatively modulating PI3K, which inhibits glycolytic metabolism and leads to a diminishing lactate production by these cells. These effects are more pronounced in cancer cells exposed to conditioned media of M2-polarized macrophages. Moreover, clotrimazole inhibits tumor growth in a murine model of implanted melanoma, reduces lactate content in a tumor microenvironment and decreases vascular endothelial growth factor expression. Finally, clotrimazole drastically diminishes TAM infiltration in the tumors, thereby inducing M1 polarization. Collectively, these findings identify a new antitumor mechanism of clotrimazole by modulating the tumor microenvironment (TME), particularly the activation and viability of TAM.
Asunto(s)
Clotrimazol/farmacología , Melanoma Experimental/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Animales , Antineoplásicos , Línea Celular Tumoral , Polaridad Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Melanoma Experimental/genética , Melanoma Experimental/patología , Ratones , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Macrófagos Asociados a Tumores/efectos de los fármacosRESUMEN
Among the principal causative factors for the development of complications related to aging is a diet rich in fats and sugars, also known as the Western diet. This diet advocates numerous changes that might increase the susceptibility to initiate cancer and/or to create a tissue microenvironment more conducive to the growth of malignant cells, thus favoring the progression of cancer and metastasis. Hypercaloric diets in general lead to oxidative stress generating reactive oxygen species and induce endoplasmic reticulum stress. Our results demonstrate that mice bearing tumors fed with a Western diet presented bigger tumor mass with increased insulin sensitivity in these tissues. Several markers of insulin signaling, such as AKT phosphorylation and mTOR pathway, are promoted in tumors of Western diet-fed animals. This process is associated with increased macrophage infiltration, activation of unfolded protein response pathway, and initiation of epithelial-mesenchymal transition (EMT) process in these tumor tissues. Summing up, we propose that the Western diet accelerates the aging-related processes favoring tumor development.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Dieta Occidental/efectos adversos , Transición Epitelial-Mesenquimal , Mediadores de Inflamación/metabolismo , Melanoma Experimental/metabolismo , Neoplasias Cutáneas/metabolismo , Respuesta de Proteína Desplegada , Factores de Edad , Animales , Línea Celular Tumoral , Proliferación Celular , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones Endogámicos C57BL , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transducción de Señal , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo , Factores de Tiempo , Carga Tumoral , Microambiente Tumoral , Respuesta de Proteína Desplegada/genéticaRESUMEN
AIMS: AMPK plays a critical role regulating cell metabolism, growth and survival. Interfering with this enzyme activity has been extensively studied as putative mechanism for cancer therapy. The present work aims to identify a specific AMPK activator for cancer cells among a series of novel heterocyclic compounds. MATERIALS AND METHODS: A series of novel hybrid heterocyclic compounds, namely naphtoquinone-4-oxoquinoline and isoquinoline-5,8-quinone-4-oxoquinoline derivatives, were synthesized via Michael reaction and their structures confirmed by spectral data: infrared; 1H and 13C NMR spectroscopy (COSY, HSQC, HMBC); and high-resolution mass spectrometry (HRMS). The novel compounds were screened and tested for antitumoral activity and have part of their mechanism of action scrutinized. KEY FINDINGS: Here, we identified a selective AMPK activator among the new hybrid heterocyclic compounds. This new compound presents selective cytotoxicity on breast cancer cells but not on non-cancer counterparts. We identified that by specifically activating AMPK in cancer cells, the drug downregulates unfolded protein response pathway, as well as inhibits mTOR signaling. SIGNIFICANCE: These effects, that are selective for cancer cells, lead to activation of autophagy and, ultimately, to cancer cells death. Taken together, our data support the promising anticancer activity of this novel compound which is a strong modulator of metabolism.