Department of Biochemistry and Molecular Medicine, Graduate School, Biomedical Science Institute, Kyung Hee University, Seoul, Korea.
Exp Mol Med. 2020 Dec;52(12):2055-2068. doi: 10.1038/s12276-020-00541-3. Epub 2020 Dec 18.
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.
多柔比星是最有效的抗癌药物之一，但其具有心脏毒性等不良反应，临床应用受到限制。多柔比星诱导的细胞毒性的一个标志是线粒体功能障碍。尽管近几十年来进行了深入研究，但尚无有效方法可减轻多柔比星诱导的细胞毒性。褪黑素是一种主要由松果体分泌的天然激素，由于其维持线粒体完整性的药物作用，作为一种有前途的佐剂，可预防多柔比星诱导的细胞毒性。然而，其潜在机制仍远未完全清楚。在这里，我们提供了新的证据表明，用多柔比星处理 H9c2 心肌细胞强烈诱导 AMP 激活的蛋白激酶α2（AMPKα2），其转位到线粒体并干扰其功能和完整性，最终导致细胞凋亡。褪黑素处理显著阻断了这些现象。在多柔比星和褪黑素处理的情况下，鼠心中 AMPKα2 的水平与心脏毒性密切相关。因此，我们的研究表明，维持线粒体完整性是减轻多柔比星诱导的细胞毒性的关键因素，并表明 AMPKα2 可能成为包括多柔比星在内的细胞保护联合治疗设计中的一个新的靶标。
