RESUMEN
BACKGROUND: Glioblastomas are the most devastating brain tumor characterized by chemoresistance development and poor prognosis. Macrophages are a component of tumor microenvironment related to glioma malignancy. The relation among inflammation, innate immunity and cancer is accepted; however, molecular and cellular mechanisms mediating this relation and chemoresistance remain unresolved. OBJECTIVE: Here we evaluated whether glioma sensitive or resistant to temozolomide (TMZ) modulate macrophage polarization and inflammatory pathways associated. The impact of glioma-macrophage crosstalk on glioma proliferation was also investigated. METHODS: GL261 glioma chemoresistance was developed by exposing cells to increasing TMZ concentrations over a period of 6months. Mouse peritoneal macrophages were exposed to glioma-conditioned medium or co-cultured directly with glioma sensitive (GL) or chemoresistant (GLTMZ). Macrophage polarization, in vitro and in vivo glioma proliferation, redox parameters, ectonucleotidase activity and ATP cytotoxicity were performed. RESULTS: GLTMZ cells were more effective than GL in induce M2-like macrophage polarization and in promote a strong immunosuppressive environment characterized by high IL-10 release and increased antioxidant potential, which may contribute to glioma chemoresistance and proliferation. Interestingly, macrophage-GLTMZ crosstalk enhanced in vitro and in vivo proliferation of chemoresistant cells, decreased ectonucleotidase activities, which was followed by increased macrophage sensitivity to ATP induced death. CONCLUSIONS: Results suggest a differential macrophage modulation by GLTMZ cells, which may favor the maintenance of immunosuppressive tumor microenvironment and glioma proliferation. GENERAL SIGNIFICANCE: The induction of immunosuppressive environment and macrophage education by chemoresistant gliomas may be important for tumor recovery after chemotherapy and could be considered to overcome chemoresistance development.
Asunto(s)
Dacarbazina/análogos & derivados , Resistencia a Antineoplásicos/genética , Glioma/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Animales , Antineoplásicos Alquilantes/administración & dosificación , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Polaridad Celular/efectos de los fármacos , Dacarbazina/administración & dosificación , Modelos Animales de Enfermedad , Glioma/metabolismo , Glioma/patología , Humanos , Inflamación/metabolismo , Inflamación/patología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Receptores Purinérgicos/genética , Temozolomida , Microambiente Tumoral/efectos de los fármacosRESUMEN
Glioblastoma multiforme (GBM) is the worst form of primary brain tumor, which has a high rate of infiltration and resistance to radiation and chemotherapy, resulting in poor prognosis for patients. Recent studies show that thiazolidinones have a wide range of pharmacological properties including antimicrobial, anti-inflammatory, anti-oxidant and anti-tumor. Here, we investigate the effect antiglioma in vitro of a panel of sixteen synthetic 2-aryl-3-((piperidin-1-yl)ethyl)thiazolidin-4-ones where 13 of these decreased the viability of glioma cells 30-65% (100 µM) compared with controls. The most promising compounds such as 4d, 4l, 4m and 4p promoted glioma reduction of viability greater than 50%, were further tested at lower concentrations (12.5, 25, 50 and 100 µM). Also, the data showed that the compounds 4d, 4l, 4m and 4p induced cell death primarily through necrosis and late apoptosis mechanisms. Interestingly, none of these 2-aryl-3-((piperidin-1-yl)ethyl)thiazolidin-4-ones were cytotoxic for primary astrocytes, which were used as a non-transformed cell model, indicating selectivity. Our results also show that the treatment with sub-therapeutic doses of 2-aryl-3-((piperidin-1-yl)ethyl)thiazolidin-4-ones (4d, 4l and 4p) reduced in vivo glioma growth as well as malignant characteristics of implanted tumors such as intratumoral hemorrhage and peripheral pseudopalisading. Importantly, 2-aryl-3-((piperidin-1-yl)ethyl)thiazolidin-4-ones treatment did not induce mortality or peripheral damage to animals. Finally, 2-aryl-3-((piperidin-1-yl)ethyl)thiazolidin-4-ones also changed the nitric oxide metabolism which may be associated with reduced growth and malignity characteristics of gliomas. These data indicates for the first time the therapeutic potential of synthetic 2-aryl-3-((piperidin-1-yl)ethyl)thiazolidin-4-ones to GBM treatment.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Encefálicas/patología , Proliferación Celular/efectos de los fármacos , Glioblastoma/patología , Modelos Biológicos , Tiazolidinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Ratas , Ratas WistarRESUMEN
Glioblastoma multiforme (GBM) is the worst and most common brain tumor, characterized by high proliferation and invasion rates. Nanoparticles of biodegradable polymers for anticancer drug delivery have attracted interest in recent years since they provide targeted delivery and may overcame the obstacle imposed by blood-brain barrier. Here we investigated the antitumoral effect of ketoprofen-loaded nanocapsules (Keto-NC) treatment on in vitro and in vivo glioma progression. We observed that Keto-NC treatment decreased selectively the cell viability of a panel of glioma cell lines, while did not exhibited toxicity to astrocytes. We further demonstrate that the treatment with sub-therapeutic dose of Keto-NC reduced the in vivo glioma growth as well as reduced the malignity characteristics of implanted tumors. Keto-NC treatment improved the weight, the locomotion/exploration behavior of glioma-bearing rats. Importantly, Keto-NC treatment neither induced mortality or peripheral damage. Finally, Ketoprofen also altered the extracellular nucleotide metabolism of peripheral lymphocytes, suggesting that antiinflammatory effects of ketoprofen could also be associated with the modulation of the adenine nucleotide metabolism in lymphocytes. Data indicate at first time the potential of Keto-NC as a promising therapeutic alterative to GBM treatment.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Antineoplásicos/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Cetoprofeno/administración & dosificación , Nanocápsulas/administración & dosificación , Animales , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Glioma/patología , Humanos , Masculino , Ratas , Ratas Wistar , Carga Tumoral/efectos de los fármacosRESUMEN
This study assessed the antiproliferative effect in vitro of the flower hexane extract obtained from Mentha spicata associated with Mentha rotundifolia against the human breast adenocarcinoma (MCF-7), human mouth epidermal carcinoma (KB), and mouse embryonic fibroblast (NIH 3T3) cell lines, using sulforhodamine B (SRB) assay. A cell density of 2×10(4)/well was seeded in 96-well plates, and samples at different concentrations ranging from 10 to 500 mg/mL were tested. The optical density was determined in an ELISA multiplate reader (Thermo Plate TP-Reader). Results demonstrated that the hexane extract presented antiproliferative activity against both the tumor cell lines KB and MCF-7, presenting a GI(50) (MCF-7=13.09 mg/mL), TGI (KB=37.76 mg/mL), and IL(50) (KB=291.07 mg/mL). Also, the hexane extract presented antiproliferative activity toward NIH 3T3 cells GI(50) (183.65 mg/mL), TGI (280.54 mg/mL), and IL(50) (384.59 mg/mL). The results indicate that the flower hexane extract obtained from M. spicata associated with M. rotundifolia presents an antineoplastic activity against KB and MCF-7, although an antiproliferative effect at a high concentration of the extract was observed toward NIH 3T3.