ER Chaperone Alleviates Doxorubicin-Induced Cardiotoxicity

Background: Doxorubicin is an effective chemotherapeutic agent for cancer treatment, but its use is often limited by cardiotoxicity. Recently, we demonstrated that endoplasmic reticulum (ER) stress signaling pathways play important roles in the pathophysiology of heart failure. Here, we evaluated the role of ER stress signaling pathways in doxorubicin-induced cardiotoxicity and examined whether ER chaperone could prevent cardiotoxicity caused by doxorubicin. Methods and Results: Using electromircroscopic analysis, ER dilatation was found to in doxorubicin-treated mice hearts, suggesting that doxorubicin may cause ER stress in the hearts. Western bolt analysis showed doxorubicin activated ER-stress sensors: activating transcription factor-6 (ATF-6) and inositol-requiring enzyme 1 (IRE1) and induced ER stress-initiated apoptotic signaling pathway: caspase-12 in both cultured cardiomyocytes and mice hearts. However, doxorubicin failed to induce ER chaperone glucose-regulated protein (GRP) 78, a protective factor against ER stress-induced cell death, which may augment ER stress in heart. Cardiac-specific overexpression of GRP78 or the chemical ER chaperone 4-phenylbutyrate (4-PBA) attenuated ER-initiated apoptosis and alleviated cardiac dysfunction in doxorubicin-treated mice hearts. Conclusions: Although doxorubicin activated ER stress sensors and ER stress-initiated apoptosis signaling, it failed to induce the ER chaperone GRP78, further augmenting ER stress in mouse hearts. The chemical ER chaperone 4-PBA could eliminate the cardiotoxicity caused by doxorubicin and may therefore facilitate the safe use of doxorubicin for cancer treatment.