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Dr. Ludmila Peres Diaz
An unexpected turn in the storyline is one of the most valuable tools novelists use to keep the audience engaged. The sudden death of a beloved character (Ned Stark) or of the one who supports the hero (Gandalf) gives the story the push it needs to move forward, allowing the character to grow and learn to survive despite suffering. Some turns are even more challenging for the audience, because the one who is supposed to bring balance turns to the dark side, and everything falls apart, hopelessness (Darth Vader). However, these are only part of the journey, and the real end depends on the hero’s resolve and on the strength of all the characters involved. They survived, conquered the darkness, and now, covered with scars, they are telling the story for those who come after them.
This metaphor conveys how and why Doxorubicin remains one of the most widely used chemotherapeutic agents in cancer treatment, with a projected market growth of USD 2 billion by 203010, despite its well-known cardiotoxicity. 1
Doxorubicin, hero and villain
Chemotherapeutics are powerful drugs that inhibit the growth of rapidly dividing cancer cells. However, these mechanisms can also harm healthy dividing cells, causing side effects. Doxorubicin (dox), an anthracycline antibiotic, is approved for the treatment of leukemia, lymphoma, and sarcoma, as well as cancers of the brain, breast, stomach, lung, ovary, bladder, thyroid, and kidney. 1,2
Dox can cause dose-dependent cardiotoxicity, leading to impaired cardiac function in 9% of patients. 2 Different mechanisms of action and several therapeutic targets, as well as palliative therapies, have been described over the years to explain dox cardiotoxicity. However, more research is needed to address the cardiac burden in surviving patients that recieved dox during their treatment.3
The duality of dox means that the treatment used to eliminate malignant cells succeeded but also caused significant damage to healthy cells, leaving deep scars and future challenges.
Dox’s mechanisms of action: savior and executioner
Dox is rapidly taken up by tissues after intravenous administration, particularly by the liver, lungs, spleen, stomach, kidneys, heart, and intestine, but does not cross the blood-brain barrier.1 Although it was initially believed that dox entered cells via diffusion, it is now known that specific transporters located on the cellular membrane, such as OCT1 and OCT3, facilitate uptake. Genetic and environmental differences in these transporters could contribute to variations in dox toxicity. 1
Once inside the cell, dox activates multiple mechanisms, including DNA damage and modification, oxygen-free and iron-mediated radical production, inflammatory cytokine production, intracellular Ca2+ overload, and mitochondrial and cellular membrane damage .1,2,3 This can take place in both healthy and cancer cells, preventing their growth, triggering apoptosis (cell death), and activating compensatory mechanisms in different organs. Notably, this includes fibrosis in the heart, which can lead to cardiovascular remodeling and promote the early development of cardiovascular disease. 4
Novel Therapeutic Strategies: controlling the unleashed fury
Since dox remains an effective chemotherapeutic agent, pharmacological and non-pharmacological approaches have been tested to prevent or alleviate the cardiac burden it can induce.
Among the pharmacological interventions tested to treat dox-induced cardiotoxicity are metformin and statins. These drugs activate the AMPK signaling pathway in cardiac muscle, a master regulator of cardiac metabolism, and present cardioprotective effects. Additionally, β-adrenergic blockers and angiotensin converting enzyme (ACE) inhibitors help preserve diastolic heart function in subjects treated with dox, while left ventricular contraction remains unchanged. However, the precise mechanisms by which β-adrenergic blockers and ACE inhibitors act, especially how they enhance cardiac muscle contraction, remain incompletely understood.2
Among the non-pharmacological approaches evaluated, exercise showed protection against dox-induced cardiac damage. Recent findings show that this protective effect is mediated by increased expression of a particular receptor in B cells, which plays a key role in reducing inflammation. Exercise interventions also decrease fatigue and enhance quality of life in patients with solid tumors and hematological malignancies. However, there is a lack of awareness regarding exercise guidelines, appropriate timing, and referral to these programs.5
New Molecular Targets: the shield against the inevitable
Many efforts are underway to identify new molecular targets and elucidate their mechanisms of action to help prevent dox-induced cardiotoxicity.
Cardiac thyrotropin-releasing hormone (cTRH) is a hormone produced by cardiac cells that promotes hypertrophy and fibrosis. It has been shown that dox increases cTRH in animal models, leading to early apoptosis and cardiac remodeling. Additionally, cTRH suppression prevents dox cardiotoxicity, reducing fibrosis and hypertrophy, suggesting a direct link between the two. Although its exact mechanism remains unknown, cTRH is a novel potential therapeutic target. 4
CREG1 is a glycoprotein that functions as a regulator of cellular differentiation, senescence, and homeostasis, primarily by repressing E1A-stimulated genes. It serves as a cardioprotective factor crucial for preserving cardiomyocyte differentiation and homeostasis. CREG1 reduces dox-induced cardiotoxicity by preventing iron-dependent apoptosis in heart cells.6
Semaglutide (SEMA), a new analog of glucagon-like peptide-1 (GLP-1), is widely recognized for its role in treating diabetes. Recent evidence also suggests it has beneficial effects on heart health. Semaglutide helps counteract dox-induced mitochondrial and cardiac dysfunction by activating the PI3K/AKT pathway and reducing BNIP3 levels in mitochondria. Improved mitochondrial performance reduces dox-induced cardiac damage and enhances cardiac function. Consequently, semaglutide may serve as a promising therapy to prevent acute heart damage caused by dox. 7
WGX50, a small-molecule compound derived from a food flavoring and traditional herbal medicine in China, demonstrates anti-inflammatory and antioxidant properties. It safeguards against dox-induced cardiotoxicity by lowering mitochondrial reactive oxygen species (ROS) levels and iron-dependent apoptosis. In animal models, WGX50 successfully mitigates cardiac dysfunction, injury, fibrosis, mitochondrial damage, and imbalance of oxygen-free radicals caused by dox .8
Galangin (Gal), a flavonoid, has demonstrated potential cardioprotective effects. It may inhibit iron-dependent apoptosis and guard against dox-induced cardiotoxicity by modulating the GSTP1/JNK pathway. 9
These advances prove that, even though there is still a long way to go, we are on the right path to enhance oncological treatment using dox, while aiming to prevent and alleviate the cardiovascular burden associated with it, and ultimately to provide a better quality of life for survivors and patients undergoing treatment.
Header Image Source: created with Canva by Jessica Desamero, using images from Wikimedia Commons and Picryl (both images are under Creative Commons licenses)
Edited by Madeline Morrison
References
1. Jones IC, Dass CR. Doxorubicin-induced cardiotoxicity: causative factors and possible interventions. J Pharm Pharmacol. 2022;74(12):1677-1688. doi:10.1093/jpp/rgac063
2. Rawat PS, Jaiswal A, Khurana A, Bhatti JS, Navik U. Doxorubicin-induced cardiotoxicity: an update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother. 2021;139:111708. doi:10.1016/j.biopha.2021.111708
3. Sheibani M, Azizi Y, Shayan M, et al. Doxorubicin-induced cardiotoxicity: an overview on pre-clinical therapeutic approaches. Cardiovasc Toxicol. 2022;22(4):292-310. doi:10.1007/s12012-021-09712-1
4. Peres Diaz LS, Schuman ML, Aisicovich M, et al. Short-term doxorubicin cardiotoxic effects: involvement of cardiac thyrotropin releasing hormone system. Life Sci. 2020;261:118346. doi:10.1016/j.lfs.2020.118346
5. [Author missing in source text]. Current evidence on the benefit of exercise in cancer patients: effects on cardiovascular mortality, cardiotoxicity, and quality of life. Rev Cardiovasc Med. 2023;24(6):160. doi:10.31083/j.rcm2406160
6. Liu D, Cheng X, Wu H, et al. CREG1 attenuates doxorubicin-induced cardiotoxicity by inhibiting the ferroptosis of cardiomyocytes. Redox Biol. 2024;75:103293. doi:10.1016/j.redox.2024.103293
7. Li X, Luo W, Tang Y, et al. Semaglutide attenuates doxorubicin-induced cardiotoxicity by ameliorating BNIP3-mediated mitochondrial dysfunction. Redox Biol. 2024;72:103129. doi:10.1016/j.redox.2024.103129
8. Tai P, Chen X, Jia G, et al. WGX50 mitigates doxorubicin-induced cardiotoxicity through inhibition of mitochondrial ROS and ferroptosis. J Transl Med. 2023;21(1):823. doi:10.1186/s12967-023-04715-1
9. Shu G, Chen K, Li J, et al. Galangin alleviated doxorubicin-induced cardiotoxicity by inhibiting ferroptosis through GSTP1/JNK pathway. Phytomedicine. 2024;134:155989. doi:10.1016/j.phymed.2024.155989
10. Research and Markets. Doxorubicin market outlook 2026-2030 & 2035: predicted to surge to $2 billion by 2030, bolstered by expanding access to cancer care. Yahoo Finance. April 1, 2026. Accessed April 29, 2026. https://sg.finance.yahoo.com/news/doxorubicin-market-outlook-2026-2030-103700173.html
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