RESUMEN
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
Melanoma is the most aggressive and fatal type of skin cancer due to being highly proliferative. Acetylsalicylic acid (ASA; Aspirin) and salicylic acid (SA) are ancient drugs with multiple applications in medicine. Here, we showed that ASA and SA present anticancer effects against a murine model of implanted melanoma. These effects were also validated in 3D- and 2D-cultured melanoma B16F10 cells, where the drugs promoted pro-apoptotic effects. In both in vivo and in vitro models, SA and ASA triggered endoplasmic reticulum (ER) stress, which culminates with the upregulation of the pro-apoptotic transcription factor C/EBP homologous protein (CHOP). These effects are initiated by ASA/SA-triggered Akt/mTOR/AMPK-dependent activation of nitric oxide synthase 3 (eNOS), which increases nitric oxide and reactive oxygen species production inducing ER stress response. In the end, we propose that ASA and SA instigate anticancer effects by a novel mechanism, the activation of ER stress.
Asunto(s)
Apoptosis/efectos de los fármacos , Aspirina/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Melanoma/etiología , Melanoma/patología , Óxido Nítrico/metabolismo , Ácido Salicílico/farmacología , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Antineoplásicos , Aspirina/uso terapéutico , Línea Celular Tumoral , Modelos Animales de Enfermedad , Masculino , Melanoma/tratamiento farmacológico , Ratones Endogámicos C57BL , Terapia Molecular Dirigida , Óxido Nítrico Sintasa de Tipo III/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ácido Salicílico/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Serina-Treonina Quinasas TOR/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Breast cancer is a major cause of death among women worldwide. Treatment for breast cancer involves the surgical removal of cancer tissue, followed by chemotherapy. Although the treatment is efficient, especially when the cancer is detected early, recurrence is common and is often resistant to the previous treatment. Therefore, a constant search for efficient and novel drugs for the treatment of breast cancer is mandatory. Recently, triazole derivatives have shown promising effects against different types of cancer, revealing these molecules as putative anticancer drugs. EXPERIMENTAL: We have synthesized a series of naphthotriazolyl-4-oxoquinoline derivatives and tested their activity against a human breast cancer cell line. Among the compounds tested, we identified a molecule that killed the human breast cancer cell line MCF-7 with minimal effects on its noncancer counterpart, MCF10A. This effect was seen after 24 hours of treatment and persisted for additional 24 hours after treatment withdrawal. After 1 hour of treatment, the compound, here named 12c, promoted a decrease in cell glucose consumption and lactate production. Moreover, the cells treated with 12c for 1 hour showed diminished intracellular ATP levels with unaltered mitochondrial potential and increased reactive oxygen species production. Additionally, apoptosis was triggered after treatment with the drug for 1 hour. All of these effects are only observed with MCF-7 cells, and not MCF10A. These data show that 12c has selective activity against breast cancer cells and is a potential candidate for a novel anticancer drug. RESULTS AND CONCLUSION: The naphthotriazolyl-4-oxoquinoline derivatives were obtained in good to moderate yields, and one of them, 12c, exhibited strong and selective antitumor properties. The antitumor mechanism involves inhibition of glycolysis, diminished intracellular ATP levels, induction of ROS production and triggering of apoptosis. These effects are all selective for cancer cells, since noncancer cells are unaffected, and these effects can only be attributed to the whole molecule, as different pharmacophoric groups did not reproduce these effects.