Abstract 3464: Vitamin D supplementation to improve doxorubicin-induced cardiotoxicity in triple negative breast cancers

Abstract

Abstract Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), which lacks the molecular targets for hormone or growth factor therapy. Although highly effective as a chemotherapeutic agent, Dox induces severe side effects including cardiotoxicity that can cause patients to stop treatment early and impact the long-term health of patients in remission. Reactive oxygen species (ROS) are the predominant contributing factor to Dox-induced cardiotoxicity. Here, we sought to use the antioxidant vitamin D to provide a cardioprotective environment to prevent or reduce cardiotoxicity in a mouse model of TNBC. Supplementation with vitamin D (10,000 IU/kg) in chow for two weeks significantly increased the active vitamin D metabolite (25(OH)VD3) in plasma from 61.2 ± 4.5 nM (Mean ± SEM) to 85.0 ± 6.3 nM (P < 0.05). Supplemented and normal chow mice were then inoculated with the syngeneic 4T1 mouse model of TNBC, and subjected to 10 mg/kg Dox once per week for two weeks. Cardiotoxicity was monitored through non-invasive echocardiography weekly. After two weeks, mice on standard chow with moderate levels of vitamin D exposed to 10 mg/kg Dox showed clear signs of cardiotoxicity represented by a decrease in cardiac output from 9.7 ± 0.5 mL/min in control mice to 4.8 ± 0.9 mL/min in mice treated with Dox (P < 0.001); a decrease in ejection fraction from 49.2% ± 1.9 in control mice to 35.7% ± 5.9 in Dox mice (P < 0.05); and a decrease in fractional shortening from 24.4% ± 1.2 in control mice to 16.9% ± 3.1 in Dox mice (P < 0.05). Mice treated with Dox also showed detectable levels of cardiac troponin (0.04 ± 0.01 ng/mL) in circulating plasma indicative of cardiac damage, while troponin levels in control mice were undetectable. Vitamin D supplementation during exposure to Dox prevented cardiotoxicity in all parameters tested with levels of cardiac output of 7.4 ± 0.9 mL/min compared to 4.8 ± 0.9 mL/min in Dox mice; ejection fraction of 55.3% ± 3.4 compared to 35.7% ± 5.9 in Dox mice (P < 0.01); and fractional shortening of 28.1% ± 2.1 compared to 16.9% ± 3.1 in Dox mice (P < 0.01). Cardiac troponin levels were also undetectable similar to control mice. Vitamin D supplementation during Dox exposure resulted in cardiac function not significantly different than control, untreated mice. These data support further examination of vitamin D supplementation during chemotherapy to prevent cardiac toxicity and to enhance long-term outcome of TNBC patients. Citation Format: Kevin J. Lee, Griffin Wright, Leigh Ann Wiggins, Michele Schuler, Natalie R. Gassman. Vitamin D supplementation to improve doxorubicin-induced cardiotoxicity in triple negative breast cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3464.