Recent progress in the role of endogenous metal ions in doxorubicin-induced cardiotoxicity

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TL;DR

This review examines how endogenous metal ions like iron, copper, zinc, and calcium contribute to doxorubicin-induced cardiotoxicity (DIC) through mechanisms such as ferroptosis, oxidative stress, and mitochondrial dysfunction. It highlights that iron overload and ferroptosis are key drivers of DIC, and that copper, zinc, and calcium dysregulation also play significant roles. The clinical significance lies in identifying metal ion-targeted therapeutic strategies, including chelators, ionophores, and natural compounds, which may reduce DIC and improve the safety of doxorubicin chemotherapy.

Full summary

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**Background:** Doxorubicin (Dox) is a widely used anthracycline antibiotic effective against various cancers, including childhood leukemia, breast cancer, lymphoma, and sarcoma. However, its clinical use is limited by dose-dependent cardiotoxicity, which can lead to acute and chronic cardiomyopathy and congestive heart failure. Up to 25% of patients using Dox may experience DIC. The mechanisms of DIC are multifactorial, involving oxidative stress, apoptosis, mitochondrial dysfunction, and dysregulation of metal ions. Endogenous metal ions such as iron, copper, zinc, and calcium are essential for normal physiological functions, but their imbalance can exacerbate DIC. This review summarizes recent progress on the roles of these metal ions in DIC and potential therapeutic strategies targeting them.

**Methods:** This is a narrative review that synthesizes findings from preclinical studies (in vivo and in vitro) and clinical observations. The authors searched for and analyzed literature on the involvement of iron, copper, zinc, and calcium in DIC, focusing on mechanisms such as ferroptosis, oxidative stress, and mitochondrial dysfunction. They also reviewed therapeutic interventions including metal chelators, ionophores, coordination compounds, and natural products that modulate metal ion homeostasis to alleviate DIC.

**Key Results:** - **Iron and Ferroptosis:** Iron overload is a critical factor in DIC. Dox promotes iron accumulation in mitochondria, leading to ferroptosis, a form of regulated cell death dependent on iron and reactive oxygen species (ROS). Key regulators include GPX4, GSH/GSSG, System Xc-, Nrf2-KEAP1, and AMPK. Dox reduces GPX4 and GSH levels, while increasing lipid peroxidation. Iron chelators such as Ferrostatin-1, Dexrazoxane, Deferoxamine, and Deferiprone have shown protective effects in animal models. For example, Ferrostatin-1 (1 mg/kg) reduced Dox-induced cell mortality and improved LVEF and LVFS in mice. Overexpression of the mitochondrial iron efflux pump ABCB8 also prevented DIC. - **Copper:** Copper contributes to DIC through redox cycling and DNA damage. Dox causes DNA damage in the presence of Cu2+, with 8-oxodG formation being greater than with cytochrome P450 reductase. Copper chelators (e.g., D-pen, trientine, tetrathiomolybdate) inhibit angiogenesis and reduce tumor growth. Copper ionophores (e.g., Cu2+(gtsm), clioquinol, disulfiram) redistribute intracellular copper and induce apoptosis in cancer cells. Copper coordination compounds, such as CuSn2, show anticancer activity with lower toxicity than cisplatin. - **Zinc:** Intracellular zinc levels ([Zn2+]i) increase in Dox-treated H9c2 cells, inducing endoplasmic reticulum (ER) stress. Zinc transporters (ZIP7 and ZnT7) regulate zinc homeostasis. Metallothionein (MT) overexpression protects against DIC by reducing oxidative stress and apoptosis. For example, cardiac-specific MT overexpression in mice inhibited Dox-induced cardiac hypertrophy and myocardial injury. Zinc supplementation (e.g., zinc-taurine, Zn2+-curcumin) also alleviated DIC. - **Calcium:** Calcium dysregulation in DIC involves ER stress and mitochondrial dysfunction. Dox increases Ca2+ release from the sarcoplasmic reticulum (SR), leading to apoptosis. Calcium channel blockers like Nicorandil and Diltiazem reduce calcium overload and protect the heart. Levosimendan, a calcium sensitizer, activates the cAMP-PKA-PLN axis, reduces calcium overload, and improves cardiac function. For instance, Levosimendan (24 μg/kg) decreased myocardial fibrosis and ROS accumulation in mice.

**Clinical Implications:** The review underscores the potential of targeting metal ion homeostasis to mitigate DIC. While Dexrazoxane is the only clinically approved iron chelator for DIC, other agents like Ferrostatin-1 and UAMC-3203 show promise but require further development. Copper chelators and ionophores may offer dual benefits by reducing DIC and inhibiting tumor growth. Zinc and calcium modulators also represent viable therapeutic avenues. However, metal ions have a "double-edged sword" nature, and excessive modulation may cause toxicity. Future research should focus on developing specific, stable, and bioavailable metal ion-targeted drugs that can cross the blood-brain barrier and selectively chelate or modulate metal ions without disrupting normal physiology. Clinical trials are needed to translate these preclinical findings into effective treatments for patients receiving Dox chemotherapy.