Investigation of the effect of atp sensitive potassium channels on doxorubicin-induced cardiotoxicity

Doxorubicin (DOX) is a drug for solid tissue cancer treatment. However, it has some side effects on non-cancerous cells. Treatment for its undesirable cytotoxicity is still not found. DOX cytotoxicity might be related to reactive oxygen species (ROS) and mitochondrial dysfunction. Protective effects of ATP-sensitive potassium channels (KATP) has been well documented against some pathological conditions, including ischemia-reperfusion. This study aimed to investigate whether the opening of KATP reverses the cardiotoxicity of DOX. Rat cardiomyocyte cell line (H9c2) was exposed for 24 hours to its medium served as control; Diazoxide (DIA), one of KATP opener; DOX, and DIA plus DOX. Distribution of actin filaments, mitochondrial membrane potential (MMP), superoxide dismutase (SOD) enzyme activity and some protein expressions were analyzed with proper tests and then statistical analysis was performed. Although DOX decreased SOD enzyme activity, AMPK protein levels and increased the ERK1/2 protein levels, DIA co-treatment restored them. DOX destroyed cytoskeleton via actin distribution, but DIA ameliorated the distribution as well. Although DOX elevated MMP, DIA reversed the DOX's effect on MMP. Cardiomyocytes loss by oxidative stress-mediated apoptosis is an important mechanism for DOX-induced cytotoxicity, and the alternations were attenuated with DIA co-treatment. Consequently, the opening of KATP has protective effects on DOX-induced cardiotoxicity and DIA may be a candidate agent to protect the cell in DOX chemotherapy. Key Words: ATP sensitive potassium channels; AMP-activated kinase; Doxorubicin; Diazoxide