title: Ruta graveolens L. induces death of glioblastoma cells and neural progenitors, but not of neurons, via ERK 1/2 and AKT activation.
abstract: Glioblastoma multiforme is a highly aggressive brain tumor whose prognosis is very poor. Due to early invasion of brain parenchyma, its complete surgical removal is nearly impossible, and even after aggressive combined treatment (association of surgery and chemo- and radio-therapy) five-year survival is only about 10%. Natural products are sources of novel compounds endowed with therapeutic properties in many human diseases, including cancer. Here, we report that the water extract of Ruta graveolens L., commonly known as rue, induces death in different glioblastoma cell lines (U87MG, C6 and U138) widely used to test novel drugs in preclinical studies. Ruta graveolens' effect was mediated by ERK1/2 and AKT activation, and the inhibition of these pathways, via PD98058 and wortmannin, reverted its antiproliferative activity. Rue extract also affects survival of neural precursor cells (A1) obtained from embryonic mouse CNS. As in the case of glioma cells, rue stimulates the activation of ERK1/2 and AKT in A1 cells, whereas their blockade by pharmacological inhibitors prevents cell death. Interestingly, upon induction of differentiation and cell cycle exit, A1 cells become resistant to rue's noxious effects but not to those of temozolomide and cisplatin, two alkylating agents widely used in glioblastoma therapy. Finally, rutin, a major component of the Ruta graveolens water extract, failed to cause cell death, suggesting that rutin by itself is not responsible for the observed effects. In conclusion, we report that rue extracts induce glioma cell death, discriminating between proliferating/undifferentiated and non-proliferating/differentiated neurons. Thus, it can be a promising tool to isolate novel drugs and also to discover targets for therapeutic intervention.
authors.affiliation: Laboratory of Molecular and Cellular Pathology, Department of Environmental, Biological and Pharmaceutical Science and Technologies, Second University of Naples, Caserta, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Gentile
authors.affiliation: Laboratory of Molecular and Cellular Pathology, Department of Environmental, Biological and Pharmaceutical Science and Technologies, Second University of Naples, Caserta, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ciniglia
authors.affiliation: Laboratory of Molecular and Cellular Pathology, Department of Environmental, Biological and Pharmaceutical Science and Technologies, Second University of Naples, Caserta, Italy.
authors.forename: Mafalda G
authors.initials: MG
authors.lastname: Reccia
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Naples, Italy; Institute of Genetics and Biophysics "Adriano Buzzati Traverso", CNR, Naples, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Volpicelli
authors.affiliation: Section of Pharmacology, Department of Internal Medicine, University of Genova, Genova, Italy, and Centro di Eccellenza per la Ricerca Biomedica (CEBR) University of Genova, Genova, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Gatti
authors.affiliation: Section of Pharmacology, Department of Internal Medicine, University of Genova, Genova, Italy, and Centro di Eccellenza per la Ricerca Biomedica (CEBR) University of Genova, Genova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Thellung
authors.affiliation: Section of Pharmacology, Department of Internal Medicine, University of Genova, Genova, Italy, and Centro di Eccellenza per la Ricerca Biomedica (CEBR) University of Genova, Genova, Italy.
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
authors.affiliation: Division of Neurology, Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy; Centro Interuniversitario per la Ricerca in Neuroscienze (CIRN), Second University of Naples, Naples, Italy.
authors.forename: Mariarosa A B
authors.initials: MA
authors.lastname: Melone
authors.affiliation: Laboratory of Molecular and Cellular Pathology, Department of Environmental, Biological and Pharmaceutical Science and Technologies, Second University of Naples, Caserta, Italy; Centro Interuniversitario per la Ricerca in Neuroscienze (CIRN), Second University of Naples, Naples, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Colucci-D'Amato
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D032105:Ruta / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D010936:Plant Extracts; D014867:Water; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3