Cytoprotective Effect of Vitamin D on Doxorubicin-Induced Cardiac Toxicity in Triple Negative Breast Cancer

• Published in: International journal of molecular sciences 2021-07, Vol.22 (14), p.7439
• Main Authors: Lee, Kevin J, Wright, Griffin, Bryant, Hannah, Wiggins, Leigh Ann, Dal Zotto, Valeria L, Schuler, Michele, Malozzi, Christopher, Cohen, Michael V, Gassman, Natalie R
• Format: Article
• Language: English
• Subjects: 4-Hydroxynonenal; Animals; Antibiotics, Antineoplastic - toxicity; antioxidant; Antioxidants; Apoptosis; Breast cancer; c-Myc protein; Calciferol; Cancer therapies; cardiology; Cardiotoxicity; Cardiotoxicity - etiology; Cardiotoxicity - pathology; Cardiotoxicity - prevention & control; Chemotherapy; Cytoprotection - drug effects; Diet; Doxorubicin; Doxorubicin - toxicity; Dynamin; Echocardiography; Ejection fraction; Enzymes; Estrogens; Female; Heart; Immunohistochemistry; Lipid peroxidation; Metabolism; Metabolites; Mice; Mice, Inbred BALB C; Mitochondria; Myc protein; NADPH quinone oxidoreductase; oncology; Oxidative stress; Phosphorylation; Protective Agents - pharmacology; Quinone oxidoreductase; Quinones; Reactive oxygen species; Serine; Stroke volume; Triple Negative Breast Neoplasms - chemically induced; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - pathology; Tumors; Vitamin D; Vitamin D - pharmacology; Vitamin D3; Vitamins - pharmacology
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22147439

Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), but its use may be limited by its cardiotoxicity mediated by the production of reactive oxygen species. We evaluated whether vitamin D may prevent Dox-induced cardiotoxicity in a mouse TNBC model. Female Balb/c mice received rodent chow with vitamin D (1500 IU/kg; vehicle) or chow supplemented with additional vitamin D (total, 11,500 IU/kg). the mice were inoculated with TNBC tumors and treated with intraperitoneal Dox (6 or 10 mg/kg). Cardiac function was evaluated with transthoracic echocardiography. The cardiac tissue was evaluated with immunohistochemistry and immunoblot for levels of 4-hydroxynonenal, NAD(P)H quinone oxidoreductase (NQO1), C-MYC, and dynamin-related protein 1 (DRP1) phosphorylation. At 15 to 18 days, the mean ejection fraction, stroke volume, and fractional shortening were similar between the mice treated with vitamin D + Dox (10 mg/kg) vs. vehicle but significantly greater in mice treated with vitamin D + Dox (10 mg/kg) vs. Dox (10 mg/kg). Dox (10 mg/kg) increased the cardiac tissue levels of 4-hydroxynonenal, NQO1, C-MYC, and DRP1 phosphorylation at serine 616, but these increases were not observed with vitamin D + Dox (10 mg/kg). A decreased tumor volume was observed with Dox (10 mg/kg) and vitamin D + Dox (10 mg/kg). Vitamin D supplementation decreased Dox-induced cardiotoxicity by decreasing the reactive oxygen species and mitochondrial damage, and did not decrease the anticancer efficacy of Dox against TNBC.