Cas Ilgly Induces Apoptosis in Glioma C6 Cells In Vitro and In Vivo through Caspase-Dependent and Caspase-Independent Mechanisms

Abstract

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.

Copper in diseases and treatments, and copper‐based anticancer strategies

“…These effects were accompanied by a limited general toxicity in tumor bearing rats. 217 In cultured C6 cells, it was observed that the drug promoted an increment in ROS, which in turn caused subsequent damage to mitochondria followed by apoptosis elicited through both, caspase-dependent and caspase-independent pathways. 217 In addition, COMET assay in peripheral blood lymphocytes and HeLa cells suggested a potential DNA damage that seemed related to the nature of the substituents on the chelate structure.…”

“…217 In addition, COMET assay in peripheral blood lymphocytes and HeLa cells suggested a potential DNA damage that seemed related to the nature of the substituents on the chelate structure. 217 Escriba`et al 218 have described the synthesis, structural characterization, and biological activity of a ternary copper(II) complex with phen and an amino acid conjugated with orthoiodohippurate (10a), which generated [Cu(phen) 2 ] 1 in aqueous solution without the addition of any external reductant, possibly by an intramolecular redox process in the presence of oxygen. (10a) was able to cleave pBR322 plasmidic DNA confirming the nuclease effect.…”

Nanoformulations of a Potent copper-based Aquaporin Inhibitor With Cytotoxic Effect Against Cancer Cells

“…Hence, different human and murine cell lines were considered, aiming at establishing murine models of melanoma and/or colon cancer. [20][21][22][23]. For these copper-based drugs, still the mechanism of action is not fully elucidated; most importantly, a number of side effects have been reported, including hematotoxicity [24].…”

Potential of Casiopeínas® Copper Complexes and Antituberculosis Drug Combination against <b><i>Mycobacterium tuberculosis</i></b>

“…All of these properties were considered with advances in the design of copper(II) coordination compounds that have been recorded and patented [13] under the name Casiopeínas® (Trademark Casiopeína Reg. 407543 SECOFI; 1992, Re.…”