Lactate Can Modulate the Antineoplastic Effects of Doxorubicin and Relieve the Drug’s Oxidative Damage on Cardiomyocytes

SIMPLE SUMMARY: Cancer cells are characterized by massive glucose consumption, leading to increased lactate generation. Once considered a waste product, this metabolite was recently shown to take part in the regulation of gene expression. The regulatory properties of lactate were also found to play a role in fostering drug resistance. In this paper, we examined whether the exposure of cancer cells to increased lactate levels can affect the anticancer efficacy of doxorubicin. Doxorubicin is a widely used drug, whose clinical application is often hampered by severe cardiotoxicity. We found that lactate can offer protection against oxidative damage caused by the drug. Interestingly, oxidative damage is reputed secondary to the antineoplastic action of the drug but plays an important role in mediating its cardiotoxic effects. ABSTRACT: Background: Doxorubicin (DOXO) is currently administered as the first-choice therapy for a variety of malignancies. Cancer cells exhibit enhanced glycolysis and lactate production. This metabolite affects gene expression and can play a role in chemoresistance. Aim of this study: We investigated whether the enhanced lactate levels that characterize neoplastic tissues can modify the response of cancer cells to DOXO. Methods: After exposing cancer cells to increased lactate levels, we examined whether this metabolite could interfere with the principal mechanisms responsible for the DOXO antineoplastic effect. Results: Increased lactate levels did not affect DOXO-induced topoisomerase poisoning but offered protection against the oxidative damage caused by the drug. This protection was related to changes in gene expression caused by the combined action of DOXO and lactate. Oxidative damage significantly contributed to the heavy cardiotoxicity following DOXO treatment. In cultured cardiomyocytes, we confirmed that DOXO-induced DNA damage and oxidative stress can be significantly mitigated by exposing the cells to increased lactate levels. Conclusions: In addition to contributing to elucidating the effects of the combined action of DOXO and lactate, our results suggest a possible method to reduce the heavy drug cardiotoxicity, a major side effect leading to therapy discontinuation.