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.
Highlights
Doxorubicin is one of the most potent chemotherapeutic agents and is widely used for the treatment of various cancers and hematological malignancies
We described a novel role for AMPKα2 in the context of the treatment of mouse embryonic fibroblasts (MEFs) with doxorubicin, showing that AMPKα2 expression is robustly induced by doxorubicin at the transcriptional level via the transcription factor E2F1 and subsequently contributes to apoptosis[24]
Melatonin blocked the induction of AMPKα2 by doxorubicin (Fig. 1b), which occurred at the transcriptional level, as evidenced by increases in AMPKα2 mRNA levels and promoter activity (Fig. 1c, d)
Summary
Doxorubicin is one of the most potent chemotherapeutic agents and is widely used for the treatment of various cancers and hematological malignancies. The more widespread use of this agent is limited owing to its severe adverse effects, including cardiotoxicity, neurological disturbances, and bone marrow aplasia[1,2]. To alleviate doxorubicin-induced toxicity, researchers have tested a number of strategies, including the Official journal of the Korean Society for Biochemistry and Molecular Biology. Yang et al Experimental & Molecular Medicine (2020) 52:2055–2068 against several chemotherapeutic agents[10,11,12]. These beneficial effects of melatonin are largely associated with its ability to prevent mitochondrial dysfunction and its strong antioxidant properties[13,14,15]. Melatonin shows great promise for use in this therapeutic context
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