Melatonin prevents doxorubicin-induced cardiotoxicity through suppression of AMPKα2-dependent mitochondrial damage

Abstract

The clinical application of doxorubicin, one of the most effective anticancer drugs, has been limited due to its adverse effects, including cardiotoxicity. One of the hallmarks of doxorubicin-induced cytotoxicity is mitochondrial dysfunction. Despite intensive research over recent decades, there are no effective approaches for alleviating doxorubicin-induced cytotoxicity. Melatonin, a natural hormone that is primarily secreted by the pineal gland, is emerging as a promising adjuvant that protects against doxorubicin-induced cytotoxicity owing to its pharmaceutical effect of preserving mitochondrial integrity. However, the underlying mechanisms are far from completely understood. Here, we provide novel evidence that treatment of H9c2 cardiomyoblasts with doxorubicin strongly induced AMP-activated protein kinase α2 (AMPKα2), which translocated to mitochondria and interfered with their function and integrity, ultimately leading to cellular apoptosis. These phenomena were significantly blocked by melatonin treatment. The levels of AMPKα2 in murine hearts were tightly associated with cardiotoxicity in the context of doxorubicin and melatonin treatment. Therefore, our study suggests that the maintenance of mitochondrial integrity is a key factor in reducing doxorubicin-induced cytotoxicity and indicates that AMPKα2 may serve as a novel target in the design of cytoprotective combination therapies that include doxorubicin.

Berberine Alleviates Doxorubicin-Induced Myocardial Injury and Fibrosis by Eliminating Oxidative Stress and Mitochondrial Damage via Promoting Nrf-2 Pathway Activation

“…It has been suggested that increased oxidative stress, such as the production of ROS, and compromise of the antioxidant system play pivotal roles in the disturbance of cardiac homeostasis in DOX-induced cardiotoxicity [ 43 , 44 ]. Mitochondria are the main sites of ROS generation and the key targets of DOX [ 45 ]. Therefore, exploring ways to inhibit oxidative stress and protect mitochondria is an attractive approach to reduce cardiac injury after DOX treatment.…”

A Hydrodistillate of Gynostemma pentaphyllum and Damulin B Prevent Cisplatin-Induced Nephrotoxicity In Vitro and In Vivo via Regulation of AMPKα1 Transcription

“…As demonstrated in the current study, activation of AMPKα1 or maintenance of AMPKα1 levels can protect cells against cisplatin-induced toxicity. Notably, we previously reported that AMPKα2 exerts proapoptotic effects in doxorubicin-treated H9c2 cardiomyocytes by interfering with mitochondrial integrity and function and that doxorubicin induced transcription of AMPKα2 in H9c2 cells [ 20 ]. In contrast, doxorubicin inhibited the transcription of AMPKα1 in several cancer cell lines [ 15 ], observations similar to those in the current study.…”

Novel Therapeutics for Anthracycline Induced Cardiotoxicity

“…AMPKα2 is overexpressed in fibroblasts treated with doxorubicin and has been shown to activate the transcription of pro-apoptotic molecules including p27, Apaf-1, and Bim. Several studies have shown that melatonin is cardioprotective against AIC, owing to its role as a potent antioxidant and free radial scavenger (96,97). These studies also suggested that melatonin may also protect against apoptotic cardiomyocyte death, and recent data show that one of the potential mechanisms of this may be via inhibition of the upstream pathways of AMPKα2 transcription (97).…”