Diallyl trisulfide suppresses doxorubicin-induced cardiomyocyte apoptosis by inhibiting MAPK/NF-κB signaling through attenuation of ROS generation.

BACKGROUND: Doxorubicin (Dox) is an effective anticancer agent. However, its effectiveness is limited by its cardiotoxic effects. It has also been reported that the mitogen-activated protein kinase family and NF-κB can be activated by Dox treatment. DATS has been shown to be a potent antioxidant with cardioprotective effects. We investigate whether Dox induces cardiac apoptosis through JNK- and ERK-dependent NF-κB upregulation that can be reduced by DATS treatment. METHODS AND MATERIAL: H9c2 cells were treated with 0.5-1.5 µM Dox for 24 hours. Dox promoted apoptosis and ROS generation and inhibited viability in a dose-dependent manner. Then, the phosphorylation levels of JNK, ERK, and NF-κB evaluated by western blot were elevated. We used inhibitors of JNK, ERK, and NF-κB to determine which of these proteins were involved in Dox-induced apoptosis. Furthermore, Dox-exposed cells were treated with DATS at doses of 1, 5, and 10 µM, and the data demonstrated that ROS generation and apoptotic proteins were decreased and that ERK and NF-κB were downregulated in a dose-dependent manner. Additionally, six-week-old rats were divided into three groups (n = 6 per group) designed as an eight-week study. Normal, Dox (at dose 3.75 mg/kg by ip) administered with or without DATS (at dose 40 mg/kg by gavage) treatment groups. The results indicate that cardiac dysfunction, apoptosis, and JNK, ERK, and NF-κB activation by Dox were reversed by treatment with DATS. CONCLUSION: DATS appears to suppress Dox-induced cardiomyocyte apoptosis by inhibiting NADPH oxidase-related ROS production and the downstream JNK/ERK/NF-κB signaling pathway; DATS may possess clinical therapeutic potential by blocking Dox-induced cardiotoxicity.