Purple corn anthocyanins prevent Doxorubicin-induced cardiotoxicity modulating the NF-κB pathway in HL-1 cardiomyocytes

Background Doxorubicin (Doxo) is an effective chemotherapeutic agent with a wide spectrum of action on different hematological and solid tumors. Its use is limited by a cumulative dose-dependent cardiotoxicity that can cause progressive cardiomyopathy and heart failure up to 10-15 years after the last chemotherapy[1]. To date, no effective strategies that can counteract cardiotoxicity and can be applied to all oncological patients are available. Thus, it is of utmost importance to find novel compounds able to prevent chronic cardiotoxicity without altering the Doxo anti-cancer activity, especially in pediatric cancer survivors. Moreover, since the molecular mechanisms involved are multiple and not completely explored, a better understanding of pathways involved might lead to the development of better and complementary cardioprotective strategies. Among the molecular mechanisms by which Doxo exerts its cardiotoxicity, NF-κB driven inflammation is emerging[2]. Interestingly, anthocyanins are a class of flavonoids widely present in the human diet and known for their cardioprotective and anti-inflammatory activity through the modulation of NF-κB[3-4]. In particular, anthocyanins have shown cardioprotective properties in mice fed an anthocyanin-rich diet based on purple corn treated with Doxo, especially compared to mice fed with an anthocyanin-free diet based on yellow corn[5]. Objectives We aimed at studying the molecular mechanisms by which purple corn anthocyanins counteracted Doxo-induced cardiotoxicity in vitro, focusing on inflammation. Methods HL-1 murine cardiomyocytes were pre-treated with extracts from two near-isogenic corn lines (yellow and purple corn) which differ only for the ability to produce and accumulate anthocyanins. This allowed us to study the anti-inflammatory effect of anthocyanins in the whole extract, but discriminating whether it was due to anthocyanins themselves, only in purple corn extract (Red), or to other flavonoids in both Red and Yellow extracts. In order to evaluate the preventive effect of anthocyanins on Doxo-induced NF-κB inflammatory pathway, HL-1 cardiomyocytes were then co-treated with extracts and Doxo at two different concentrations which mimic the plasmatic doses of Doxo found in treated patients. Results Our results showed that Red extract was able to restore cell viability after Doxo treatment, exerting cytoprotective activity. Furthermore, Doxo induced inflammation in HL-1 cardiomyocytes, promoting the nuclear translocation of NF-κB and inducing the expression of its downstream pro-inflammatory mediators, such as iNOS, COX-2, nitric oxide, PGE2 and cytokines. On the contrary, the treatment with Red prevented the nuclear translocation of NF-κB, leading to a reduction of Doxo-induced inflammatory mediators, whereas Yellow had little or no effect. Conclusion Our results showed that the pro-inflammatory NF-κB pathway is involved in Doxo-induced cardiotoxicity and that anthocyanins from purple corn may represent a safe and sustainable dietary supplement to prevent Doxo-induced inflammation and toxicity in cancer patients.