Anti-proliferative, pro-apoptotic and anti-invasive effect of the copper coordination compound Cas III-La through the induction of reactive oxygen species and regulation of Wnt/β-catenin pathway in glioma
Rosa Angélica Castillo‐Rodríguez, Guadalupe Palencia, Isabel Anaya‐Rubio, Juan Carlos Gallardo Pérez, Dolores Jiménez‐Farfán, Ángel Escamilla-Ramírez, Sergio Zavala-Vega, Arturo Cruz-Salgado, Claudia Cervantes-Rebolledo, Isabel Gracia‐Mora, Lena Ruíz-Azuara, Cristina Trejo‐Solís
Abstract
Gliomas are the most aggressive neoplasms that affect the central nervous system, being glioblastoma multiforme (GBM) the most malignant. The resistance of GBM to therapies is attributed to its high rate of cell proliferation, angiogenesis, invasion, and resistance to apoptosis; thus, finding alternative therapeutic approaches is vital. In this work, the anti-proliferative, pro-apoptotic, and anti-invasive effect of the copper coordination compound Casiopeina III-La (Cas III-La) on human U373 MG cells was determined in vitro and in vivo. Our results indicate that Cas III-La exerts an anti-proliferative effect, promoting apoptotic cell death and inactivating the invasive process by generating reactive oxygen species (ROS), inactivating GSK3, activating JNK and ERK, and promoting the nuclear accumulation of -catenin. The inhibition of ROS generation by N-acetyl-l-cysteine not only recovered cell migration and viability, but also reduced -catenin accumulation and JNK and ERK activation. Additionally, Cas III-La significantly reduced tumor volume, cell proliferation and mitotic indices, and increased the apoptotic index in mice xenotransplanted with U373 glioma cells. Thus, Cas III-La is a promising agent to treat GBM.