title: Copper compound induces autophagy and apoptosis of glioma cells by reactive oxygen species and JNK activation.
abstract: BACKGROUND
  Glioblastoma multiforme (GBM) is the most aggressive of the primary brain tumors, with a grim prognosis despite intensive treatment. In the past decades, progress in research has not significantly increased overall survival rate.
  
  
  METHODS
  The in vitro antineoplastic effect and mechanism of action of Casiopeina III-ia (Cas III-ia), a copper compound, on rat malignant glioma C6 cells was investigated.
  
  
  RESULTS
  Cas III-ia significantly inhibited cell proliferation, inducing autophagy and apoptosis, which correlated with the formation of autophagic vacuoles, overexpression of LC3, Beclin 1, Atg 7, Bax and Bid proteins. A decrease was detected in the mitochondrial membrane potential and in the activity of caspase 3 and 8, together with the generation of intracellular reactive oxygen species (ROS) and increased activity of c-jun NH(2)-terminal kinase (JNK). The presence of 3-methyladenine (as selective autophagy inhibitor) increased the antineoplastic effect of Cas III-ia, while Z-VAD-FMK only showed partial protection from the antineoplastic effect induced by Cas III-ia, and ROS antioxidants (N-acetylcysteine) decreased apoptosis, autophagy and JNK activity. Moreover, the JNK -specific inhibitor SP600125 prevented Cas III-ia-induced cell death.
  
  
  CONCLUSIONS
  Our data suggest that Cas III-ia induces cell death by autophagy and apoptosis, in part due to the activation of ROS -dependent JNK signaling. These findings support further studies of Cas III-ia as candidate for treatment of human malignant glioma.
authors.affiliation: Departamento de Neuroinmunología y Neuropatología, Instituto Nacional de Neurología y Neurocirugía, SSA, Insurgentes Sur 3877, México, DF, 14269, Mexico. trejosolis@yahoo.com.mx
authors.forename: Cristina
authors.initials: C
authors.lastname: Trejo-Solís
authors.forename: Dolores
authors.initials: D
authors.lastname: Jimenez-Farfan
authors.forename: Sara
authors.initials: S
authors.lastname: Rodriguez-Enriquez
authors.forename: Francisca
authors.initials: F
authors.lastname: Fernandez-Valverde
authors.forename: Arturo
authors.initials: A
authors.lastname: Cruz-Salgado
authors.forename: Lena
authors.initials: L
authors.lastname: Ruiz-Azuara
authors.forename: Julio
authors.initials: J
authors.lastname: Sotelo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D003300:Copper; D004789:Enzyme Activation / Q000187:drug effects; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009942:Organometallic Compounds / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: C525246:(4,4-dimethyl-2,2-bipyridine)(acetylacetonate)copper(II); D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D003300:Copper; D002374:Catalase; D013482:Superoxide Dismutase; D048031:JNK Mitogen-Activated Protein Kinases