Role of purple corn anthocyanins against Doxorubicin-induced cardiotoxicity: an insight into NF-κB pathway

Doxorubicin (Doxo) is a chemotherapeutic agent belonging to the anthracycline family. Despite its anticancer efficacy and its wide spectrum of action, its use is limited by a cumulative dose-dependent cardiotoxicity that can cause progressive cardiomyopathy and heart failure. Although there are a lot of effective primary and secondary prevention strategies, currently none of these seems to be relevant for all types of patients and cancers. Moreover, the majority of them shows side effects or interferes with Doxo anticancer activity reducing its effectiveness. Since inflammation has been also proposed to be involved in Doxorubicin-induced cardiomyopathy, a possible strategy to prevent cardiotoxicity would be to reduce Doxorubicin-induced inflammation. Interestingly, anthocyanins are a class of flavonoids with multiple biological activities, including cardioprotective and anti-inflammatory properties. Moreover, anthocyanins from purple corn demonstrated a protective role in mice against Doxo-induced cardiotoxicity. Given these premises, we aimed to study whether anthocyanins from purple corn could counteract Doxo-induced cardiotoxicity through the modulation of the pro-inflammatory NF-κB pathway. We used extracts from two near-isogenic maize lines (yellow and purple corn) which are genetically identical except for the gene regulators promoting the synthesis and accumulation of anthocyanins, allowing to discriminate the effect of anthocyanins, present only in Red extract, from the one of other flavonoids present in both extracts (Yellow and Red). We tested the preventive effect of Yellow and Red extracts on HL-1 murine cardiomyocytes challenged with Doxo at two different concentrations which mimic the plasmatic doses of Doxo found in patients. Our results showed that Red extract improved viability of HL-1 cardiomyocytes upon Doxo treatment and down-regulated the Doxo-induced inflammatory mediators analyzed. On the other hand, Yellow extract had always little or no effect. Thus, anthocyanins exerted this anti-inflammatory activity. Particularly, anthocyanins from purple corn showed cardioprotective activity, inhibited nuclear translocation of NF-κB and decreased levels of iNOS, COX-2, cytokines, nitric oxide and PGE2 induced by Doxo. In conclusion, supplementation with an anthocyanin-rich extract from purple corn may represent a strategy to prevent Doxo-induced inflammation and toxicity through NF-κB modulation in cancer patients.