Anti-inflammatory activity of anthocyanins from purple corn against Doxorubicin-induced cardiotoxicity

Doxorubicin (Doxo) is an effective chemotherapeutic agent with a wide spectrum of action on different haematological and solid tumors, but 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. 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. The mechanisms by which Doxo induces cardiotoxicity are multiple, but among the pathways involved Doxo-induced inflammation through NF-κB activation is emerging. Interestingly, anthocyanins (ACNs) 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. Given these premises, we aimed to study whether ACNs from purple corn could counteract Doxo-induced cardiotoxicity in HL-1 murine cardiomyocytes. We used extracts from two near-isogenic maize lines (yellow and purple corn) which are genetically identical except for the ability to synthesize and accumulate ACNs, allowing to discriminate the effect of ACNs, present only in Red extract, from the one of other flavonoids present in both extracts (Yellow and Red). HL-1 cardiomyocytes were pre-treated with Yellow or Red extracts and then challenged with Doxo at two different concentrations which mimic the plasmatic doses of Doxo found in treated patients. We analyzed the preventive effects of ACNs against Doxo-induced inflammation by analyzing the expression of pro-inflammatory genes and/or proteins, such as NF-κB, iNOS, COX-2, cytokines, and levels of nitric oxide and PGE2 in HL-1 cardiomyocytes. Our results showed that Red extract improved viability of HL-1 cardiomyocytes upon Doxo treatment and down-regulated the Doxo-induced inflammatory mediators analyzed, whereas Yellow extract had a milder or no effect. ACNs from purple corn inhibited nuclear translocation of NF-κB and decreased levels of iNOS, COX-2, cytokines, nitric oxide and PGE2 induced by Doxo treatment. In conclusion, supplementation with an ACN-rich extract from purple corn may represent a strategy to prevent Doxo-induced inflammation and toxicity through NF-κB modulation in cancer patients.