Anthracyclines, such as doxorubicin (DOX), are regarded as some of the most effective cytostatic drugs for the treatment of various malignancies. However, they pose a significant risk of acute and chronic cardiotoxicity. 1

The main mechanisms of cardiotoxicity (although not fully understood) seem to be related to anthracycline-induced reactive oxygen species (ROS) and drug-induced inhibition of topoisomerase-IIβ within cardiac myocytes. Nevertheless, other proposed mechanisms, such as mitochondrial iron accumulation, lipid peroxidation, protein nitrosylation, and calcium handling abnormalities, are being investigated, suggesting a multifactorial underlying cause. 1,2

Over the years, different strategies have been considered to prevent or reduce anthracycline-induced cardiotoxicity, such as adjusting infusion timing, delivery mode (e.g., liposomal DOX), iron chelating agents (e.g., dexrazoxane), the use of cardioprotective drugs (e.g., angiotensin-converting enzyme inhibitors, beta-blockers, and statins), and the development of novel anthracycline derivatives with little or no cardiotoxicity. 1,2

However, given the importance of anthracycline-based chemotherapy regimens, the prevention of their cardiotoxicity is still a highly unmet medical need.

In this article, Kumar et al. 3 investigated the potential therapeutic role of lactoferrin in treating doxorubicin-induced cardiotoxicity in albino rats. Lactoferrin is a glycoprotein present in body fluids and mucosal secretions of mammals with strong iron-chelating properties.

The first report linking lactoferrin to cancer was in 1994, when Bezault and coworkers presented data about the anti-cancer activity of lactoferrin in murine models of fibrosarcoma and melanoma. 4

It is postulated that lactoferrin can regulate iron availability to cancer cells—limiting their growth and progression, reducing oxidative stress, and inhibiting the mechanisms that promote carcinogenesis by chelating free Fe ions. Additionally, it exhibits immunomodulatory and anti-inflammatory effects and may enhance the body's anti-tumor response. Due to the aforementioned multidirectional anti-tumor effects, lactoferrin represents a promising therapeutic agent that may find application in both the prevention and treatment of cancer. 5

Furthermore, lactoferrin was recently found to be an ideal carrier for chemotherapeutics, even for the treatment of brain tumors, due to its ability to cross the blood–brain barrier. 6

In this well-conducted animal study by Kumar and colleagues 3, lactoferrin treatment restored hemodynamic parameters to normal levels, increased body weight and the heart weight-to-body weight ratio, and reduced the levels of cardiac biomarkers such as troponin and brain natriuretic peptide (BNP). It also restored the levels of proinflammatory cytokines such as TNF-α, IL-6, and CRP, and reversed changes in oxidative stress parameters (such as nitric oxide). These changes were reflected in thehistopathological analysis, where lactoferrin restored myocardial fiber organization, resulting in mild to moderate lesions, a low occurrence of degeneration, and the absence of necrosis in rats injected with lactoferrin 1 hour after DOX injection, compared to toxic controls.

In conclusion, the authors hypothesized that lactoferrin might play a beneficial role in modulating the production of proinflammatory cytokines and could be administered clinically as an adjunct alongside doxorubicin to reduce its cardiotoxicity. 3,

Another study in mice also demonstrated that the conjugation of lactoferrin with doxorubicin improved internalization and nuclear retention of doxorubicin in prostate cancer cells, increasing cytotoxicity with a marked reduction in tumor growth, neurotoxicity, and cardiotoxicity. It was also efficient in overcoming multi-drug resistance in an advanced drug-resistant cancer cell line. 7

The combination of lactoferrin and doxorubicin represents a promising frontier for making chemotherapy safer and more effective, but clinical trials are needed to validate these findings in vivo.