Cas IIgly induces apoptosis in glioma C6 cells in vitro and in vivo through caspase-dependent and caspase-independent mechanisms.
In this work, we investigated the effects of Casiopeina II-gly (Cas IIgly)--a new copper compound exhibiting antineoplastic activity--on glioma C6 cells under both in vitro and in vivo conditions, as an approach to identify potential therapeutic agents against malignant glioma. The exposure of C6 cells to Cas IIgly significantly inhibited cell proliferation, increased reactive oxygen species (ROS) formation, and induced apoptosis in a dose-dependent manner. In cultured C6 cells, Cas IIgly caused mitochondrio-nuclear translocation of apoptosis induction factor (AIF) and endonuclease G at all concentrations tested; in contrast, fragmentation of nucleosomal DNA, cytochrome c release, and caspase-3 activation were observed at high concentrations. Administration of N-acetyl-L-cystein, an antioxidant, resulted in significant inhibition of AIF translocation, nucleosomal DNA fragmentation, and caspase-3 activation induced by Cas IIgly. These results suggest that caspase-dependent and caspase-independent pathways both participate in apoptotic events elicited by Cas IIgly. ROS formation induced by Cas IIgly might also be involved in the mitochondrio-nuclear translocation of AIF and apoptosis. In addition, treatment of glioma C6-positive rats with Cas IIgly reduced tumor volume and mitotic and cell proliferation indexes, and increased apoptotic index. Our findings support the use of Cas IIgly for the treatment of malignant gliomas.
Trejo-Solís
Cristina
C
Departamento de Neuroinmunología, Instituto Nacional de Neurología y Neurocirugía, SSA, Mexico, DF 14269, Mexico. trejosolis@yahoo.com.mx
Palencia
Guadalupe
G
Zúñiga
Sergio
S
Rodríguez-Ropon
Andrea
A
Osorio-Rico
Laura
L
Luvia
Sanchez Torres
ST
Gracia-Mora
Isabel
I
Marquez-Rosado
Lucrecia
L
Sánchez
Aurora
A
Moreno-García
Miguel E
ME
Cruz
Arturo
A
Bravo-Gómez
María Elena
ME
Ruiz-Ramírez
Lena
L
Rodríguez-Enriquez
Sara
S
Sotelo
Julio
J
D000111:Acetylcysteine / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D003300:Copper / Q000494:pharmacology*; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000188:drug therapy*; D066298:In Vitro Techniques; D015227:Lipid Peroxidation; D008564:Membrane Potentials; D008928:Mitochondria / Q000473:pathology; D009707:Nucleosomes / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D013347:Subcellular Fractions
D000975:Antioxidants; D002843:Chromatin; D009707:Nucleosomes; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; C505569:casiopeina II-glycine; D003300:Copper; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D000111:Acetylcysteine