Apoptosis and oxidative stress of mouse breast carcinoma 4T1 and human intestinal epithelial Caco-2 cell lines caused by the phycotoxin gymnodimine-A

Abstract

Gymnodimine-A (GYM-A) is a cyclic imine phycotoxin produced by some marine dinoflagellates. It can cause rapid death of mice via intraperitoneal administration and frequently accumulate in shellfish potentially threatening human health. In this study, four different cell lines were exposed to GYM-A for the viability assessment. Results showed that GYM-A was cytotoxic with concentration-dependent pattern to each cell type, with mean IC50 values ranging from 1.39 to 2.79 μmol L−1. Results suggested that the loss of cell viability of 4T1 and Caco-2 cells was attributed to apoptosis. Furthermore, the collapse of mitochondrial membrane potential and caspases activation were observed in the GYM-A-treated cells. Reactive oxygen species (ROS) and lipid peroxides (LPO) levels were markedly increased in 4T1 and Caco-2 cells exposed to GYM-A at 2 μmol L−1, and the oxidative stress in 4T1 cells was more obvious than that in Caco-2 cells. Additionally, unusual ultrastructure impairment on mitochondria and mitophagosomes occurred in the GYM-A-treated cells. These results suggested that an ROS-mediated mitochondrial pathway for apoptosis and mitophagy was implicated in the cytotoxic effects induced by GYM-A. This is the first report to explore the cytotoxic mechanisms of GYM-A through apoptosis and oxidative stress, and it will provide theoretical foundations for the potential therapeutic applications of GYM-A.