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Abstract 450: The Role of CD38 as a Therapeutic Target for Protection Against Doxorubicin-induced Cardiotoxicity Through Nad+ Boosting


 Background:
 Doxorubicin is a chemotherapy medication used to treat several types of cancer. Its major adverse effect is cardiotoxicity, which may limit its use. Doxorubicin-induced cardiotoxicity (DIC), once developed, carries a poor prognosis. Therefore strategies to prevent or treat DIC are of paramount importance but have not yet been fully developed. Being NAD
 +
 a critical nucleotide which is involved in oxy-reduction reactions and CD38 the main NAD
 +
 -consuming enzyme responsible for NAD levels regulation and homeostasis, we aim to investigate the link of CD38 and NAD
 +
 metabolism in DIC and its potential role as a therapeutic target.
 
 
 Methods:
 We compared Wild-type (WT) control mice with WT mice treated with a single dose injection of 15 mg/kg of doxorubicin who received vehicle or an antibody that blocksCD38 ecto-enzymatic activity. We also compared genetically CD38 catalytic inactive (CI) mice treated or not with the same single dose injection.
 
 
 Results:
 Doxorubicin caused a decrease in Ejection Fraction (EF) in WT mice. We also observed that CD38 CI mice treated with doxorubicin did not have changes in EF compared to their control. When compared to WT receiving just doxorubicin, WT mice treated also with the antibody had a trend to improve EF. As for exercise performance, our results show a decrease in exercise capacity induced by doxorubicin that was reversed in the antibody group and did not happen in the CD38 CI mice treated with doxorubicin. Doxorubicin caused a decrease in heart rate variability (HRV) which was improved in the antibody treated group. Moreover, our results show a survival rate that is similar to what has been previously shown, with 50% mortality associated with doxorubicin. Blockage of CD38 activity with antibody reduced mortality in this model to approximately 20%. Mechanistically, we did not observe decreases in NAD+ levels induced by Doxorubicin. However, boost of NAD induced by blocking CD38 was related to protection against DIC.
 
 
 Conclusion:
 Our results indicate that the damage mechanism of DIC may not be related directly with NAD decrease, but NAD boosting induced by CD38 blockage seems to have a positive effect in protection against cardiac dysfunction related to this chemotherapeutic treatment.
