Open Access Highly Accessed Research article

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

Cristina Trejo-Solís1*, Dolores Jimenez-Farfan2, Sara Rodriguez-Enriquez3, Francisca Fernandez-Valverde1, Arturo Cruz-Salgado4, Lena Ruiz-Azuara4 and Julio Sotelo1

Author Affiliations

1 Departamento de Neuroinmunología y Neuropatología, Instituto Nacional de Neurología y Neurocirugía, SSA, Insurgentes Sur 3877, México, DF, 14269, Mexico

2 Facultad de Odontología, Universidad Nacional Autónoma de México, México, DF, Mexico

3 Departamento de Bioquímica, Instituto Nacional de Cardiología, SSA, México, DF, Mexico

4 Departamento de Química y Medicina Nuclear, Universidad Nacional Autónoma de México, México, DF, Mexico

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BMC Cancer 2012, 12:156  doi:10.1186/1471-2407-12-156

Published: 27 April 2012

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 NH2-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.

Keywords:
Copper compounds; Autophagy; Apoptosis; ROS; NK; Casiopeinas