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Copper compound induces autophagy and apoptosis of glioma cells by reactive oxygen species and JNK activation.

AbstractBACKGROUND:
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.
AuthorsCristina Trejo-Solís, Dolores Jimenez-Farfan, Sara Rodriguez-Enriquez, Francisca Fernandez-Valverde, Arturo Cruz-Salgado, Lena Ruiz-Azuara, Julio Sotelo
JournalBMC cancer (BMC Cancer) Vol. 12 Pg. 156 (Apr 27 2012) ISSN: 1471-2407 [Electronic] England
PMID22540380 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • (4,4-dimethyl-2,2-bipyridine)(acetylacetonate)copper(II)
  • Antineoplastic Agents
  • Organometallic Compounds
  • Reactive Oxygen Species
  • Copper
  • Catalase
  • Superoxide Dismutase
  • JNK Mitogen-Activated Protein Kinases
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Autophagy (drug effects)
  • Catalase (metabolism)
  • Cell Line, Tumor
  • Copper
  • Enzyme Activation (drug effects)
  • Glioma (metabolism)
  • Humans
  • JNK Mitogen-Activated Protein Kinases (metabolism)
  • Organometallic Compounds (pharmacology)
  • Rats
  • Reactive Oxygen Species (metabolism)
  • Superoxide Dismutase (metabolism)

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