Abstract
BACKGROUND: Although the current combination of surgery, radiation, and chemotherapy is used in the breast-cancer setting, the administration of the anticancer drugs doxorubicin and trastuzumab is associated with an increased risk of developing heart failure. The aim of this study is to determine whether dietary flaxseed is comparable and/or synergistic with the angiotensin-converting enzyme inhibitor perindopril in the treatment of doxorubicin- and trastuzumab-mediated cardiotoxicity. METHODS: In a chronic in vivo murine model (n = 110), doxorubicin and trastuzumab (8 mg/kg and 3 mg/kg, respectively) were administered weekly for 3 weeks. Following this period, the mice were randomized to daily consumption of a 10% flaxseed supplemented diet, administration of perindopril (3 mg/kg) via oral gavage, or a combination of both flaxseed and perindopril for an additional 3 weeks. RESULTS: In mice treated with doxorubicin and trastuzumab, the left ventricular ejection fraction decreased from 74% ± 4% at baseline to 30% ± 2% at week 6. Treatment with either flaxseed or perindopril, or with flaxseed and perindopril improved left ventricular ejection fraction to 52% ± 4%, 54% ± 4%, and 55% ± 3%, respectively (P < 0.05). Although histologic analyses confirmed significant loss of sarcomere integrity and vacuolization in the doxorubicin- and trastuzumab-treated mice, treatment with flaxseed or perindopril, or with flaxseed and perindopril improved myocyte integrity. Finally, the level of Bcl-2 interacting protein 3, high-mobility group box 1 protein expression, and the levels of select oxylipins, were significantly elevated in mice receiving doxorubicin and trastuzumab; these markers were attenuated by treatment with either flaxseed or perindopril, or with flaxseed and perindopril. CONCLUSIONS: Flaxseed was equivalent to perindopril at improving cardiovascular remodelling by reducing biomarkers of inflammation, mitochondrial damage, and cell death.