Anthocyanins: a possible anti-inflammatory strategy against Doxorubicin-induced cardiotoxicity?

Background: Doxorubicin is one of the most effective chemotherapeutic drug, but its use is limited by cardiotoxicity, leading to cardiomyopathy and heart failure up to 10-15 years after the last chemotherapy. 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. Thus, we aimed to study the preventive effect of anthocyanins from purple corn against Doxorubicin-induced inflammation in cardiomyocytes. 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 Red extract, or to other flavonoids in both Red and Yellow extracts. HL-1 cells were pre-treated with extracts and then challenged with Doxorubicin at two different concentrations, in order to evaluate the preventive effect of anthocyanins on Doxorubicin-induced inflammation through the analysis of the pro-inflammatory NF-κB pathway. Results: Our results showed that the two doses of Doxorubicin, which mimic the plasmatic concentrations found in patients treated with it, were able to induce inflammation in HL-1 murine cardiomyocytes, promoting the nuclear translocation of NF-κB and inducing the expression of its downstream pro-inflammatory mediators. Doxorubicin upregulated iNOS and COX-2 gene/protein expression and raised the levels of their respective products nitric oxide and PGE2. It also induced the synthesis of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β. On the contrary, the treatment with Red extract prevented the nuclear translocation of NF-κB, leading to a reduction of all the Doxorubicin-induced inflammatory mediators analyzed, whereas the Yellow extract had no or a milder effect. Beyond the anti-inflammatory activity, Red extract was also able to restore cell viability after Doxorubicin treatment, exerting cytoprotective activity as well. Conclusions: To date, there are no effective strategies to prevent Doxorubicin-induced cardiotoxicity, at least not for all types of cancer patients. 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. Our results showed that the pro-inflammatory NF-κB pathway is involved in Doxorubicin-induced cardiotoxicity and that anthocyanins from purple corn may represent a safe and sustainable dietary supplement to prevent Doxorubicin-induced inflammation and toxicity in cancer patients.