Melanocortin Receptor-4 and Glioblastoma Cells: Effects of the Selective Antagonist ML00253764 Alone and in Combination with Temozolomide In Vitro and In Vivo
| Autor: | Alessandra Ottani, Paola Orlandi, Guido Bocci, Daniela Giuliani, Francesca Vaglini, C Pardini, Francesco Pasqualetti, Teresa Di Desidero, Simone Pacini, Salvatore Guarini |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Neuroscience (miscellaneous) Mice Nude Apoptosis Biology Pharmacology Mice ML00253764 03 medical and health sciences Cellular and Molecular Neuroscience In vivo Cell Line Tumor Glioblastoma Melanocortin receptor-4 Synergism Temozolomide medicine Animals Humans Phosphorylation Protein kinase B Cell Proliferation Neurons Brain Neoplasms Cell Cycle Imidazoles Drug Synergism Cell cycle In vitro 030104 developmental biology Neurology Cell culture Receptor Melanocortin Type 4 Proto-Oncogene Proteins c-akt medicine.drug |
| Zdroj: | Molecular Neurobiology. 55:4984-4997 |
| ISSN: | 1559-1182 0893-7648 |
| Popis: | Currently, no description of melanocortin receptor-4 (MC4R) expression or activity is available in human cancer cells, including glioblastoma (GBM). The aim of this study is to evaluate the presence of MC4Rs in GBM cells and the selective inhibition of their activity through the MC4R antagonist ML00253764 alone and in association with temozolomide in vitro and in vivo. MC4R genotyping and gene expression were performed on human GBM cells (U-87 and U-118) with real-time PCR. MC4R western blotting, immunohistochemistry, and immunofluorescence were obtained in both cell lines and in human tissues. Proliferation, cell cycle, and apoptotic assays were performed with ML00253764, whereas the synergism of the simultaneous combination with temozolomide was evaluated by the combination index method. ERK1/2 and Akt phosphorylation were quantified by ELISA. In vivo experiments were performed in U-87 xenografted nude mice. Both GBM cell lines and tumor tissues expressed MC4R receptors. The selective antagonist ML00253764 determined an antiproliferative and proapoptotic activity through the inhibition of the phosphorylation of ERK1/2 and Akt. Moreover, the simultaneous combination of temozolomide and ML00253764 determined a highly synergistic effect on GBM cells. The same combination in vivo showed a strong and significant decrease of GBM tumor volumes if compared to the single drug treatments, with an excellent tolerability profile. In conclusion, MC4R is present in GBM cells and its selective inhibition determined antiproliferative and proapoptotic effects, through the inhibition of ERK1/2 and Akt phosphorylation, and the synergistic enhancement of temozolomide effects in vitro and in vivo. |
| Databáze: | OpenAIRE |
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