Abstract
Doxorubicin (DOX) is the most widely used anthracycline anticancer agent; however, its cardiotoxicity limits its clinical efficacy. Numerous studies have elucidated the mechanisms underlying DOX-induced cardiotoxicity, wherein apoptosis has been reported as the most common final step leading to cardiomyocyte death. However, in the past two years, the involvement of ferroptosis, a novel programmed cell death, has been proposed. The purpose of this review is to summarize the historical background that led to each form of cell death, focusing on DOX-induced cardiotoxicity and the molecular mechanisms that trigger each form of cell death. Furthermore, based on this understanding, possible therapeutic strategies to prevent DOX cardiotoxicity are outlined. DNA damage, oxidative stress, intracellular signaling, transcription factors, epigenetic regulators, autophagy, and metabolic inflammation are important factors in the molecular mechanisms of DOX-induced cardiomyocyte apoptosis. Conversely, the accumulation of lipid peroxides, iron ion accumulation, and decreased expression of glutathione and glutathione peroxidase 4 are important in ferroptosis. In both cascades, the mitochondria are an important site of DOX cardiotoxicity. The last part of this review focuses on the significance of the disruption of mitochondrial homeostasis in DOX cardiotoxicity.
Highlights
Drug therapy for cancer has made remarkable progress in recent years with the development of molecular-targeted drugs and immune checkpoint inhibitors alongside conventional chemotherapy
Ferroptosis is a type of pro(hiPSC-CMs) from breast cancer patients who experienced DOX-induced cardiotoxicity grammed cell death dependent is characterized by thecell accumulation of lipid were consistently more sensitiveontoiron, DOXand toxicity, with decreased survival, impaired peroxides
We found that the depletion of GSH in cardiomyocytes caused a decrease in the expression of Glutathione Peroxidase 4 (GPX4) in the mitochondria [100]
Summary
Drug therapy for cancer has made remarkable progress in recent years with the development of molecular-targeted drugs and immune checkpoint inhibitors alongside conventional chemotherapy. As the population ages and cancer treatment advances, the number of patients with both conditions has been increasing [7] In this context, the field of oncocardiology has become increasingly important in recent years [8]. This review will introduce the molecular mechanisms of DOX cardiotoxicity and anthracyclines that cause type I myocardial injury and will discuss possible countermeasures. DOX (sold under the brand name Adriamycin) is one of the most widely used anticancer drugs in cancer treatment [11] It has been used for hematopoietic tumors and solid tumors, such as breast cancer, resulting in improved cure rates and quality of life for cancer patients [12]. Ferroptosis (Figure 2), and classify them according to the molecular mechanism of each cell death
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