Is flaxseed equivalent and/or synergistic with ACE inhibition in the prevention of chemotherapy induced cardiotoxicity

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Eekhoudt, Cameron
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Background: While Doxorubicin (DOX) and Trastuzumab (TRZ) are two of the most common anti-neoplastic agents used in the treatment of breast cancer, there are cardiotoxic side effects associated with their use. Recent studies have evaluated the role of pharmaceutical agents, such as perindopril (PER), and nutraceutical agents, such as flaxseed (FLX), in the prevention of DOX+TRZ mediated cardiotoxicity. Little is known, however, on whether FLX will work comparably and/or synergistically with PER in preventing chemotherapy-induced cardiotoxicity. Objective: To determine whether prophylactic administration of FLX will work equivalently and/or synergistically with PER in the prevention of DOX+TRZ-mediated cardiotoxicity in a chronic in vivo female murine model. Methods: A total of 200 wild-type C57Bl/6 female mice were randomized to receive either regular chow (RC) or FLX-supplemented diets for a total of 6 weeks. On weeks 4, 5, and 6, mice were further randomized to receive an intraperitoneal injection of: i) 0.9% saline; ii) DOX (8mg/kg/wk); iii) TRZ (3mg/kg/wk); or iv) DOX+TRZ to create a chronic in vivo murine model of chemotherapy-induced cardiotoxicity. Within each group, mice were randomized to receive PER (3mg/kg/daily) daily via oral gavage. Weekly echocardiography and hemodynamic parameters were measured throughout the 6-week study. At study endpoint, cardiac tissues were harvested for histological and biochemical analyses. Results and Discussion: In mice treated with RC+DOX+TRZ, left ventricular end diastolic diameter (LVEDD) increased from 2.8±0.2 mm at baseline to 4.3±0.2 mm by week 6. Prophylactic administration of either PER or FLX alone partially prevented adverse left ventricular (LV) remodelling with LVEDD values of 3.4±0.3 mm and 3.5±0.2 mm, respectively. Similarly, the left ventricular ejection fraction (LVEF) in mice treated with RC+DOX+TRZ decreased from 75±2% at baseline to 37±3% at week 6. Prophylactic treatment with either PER or FLX alone partially attenuated LV systolic dysfunction with LVEF values of 63±2% and 62±2%, respectively. Prophylactic treatment with the combination of PER+FLX, however, was not synergistic at preventing adverse LV remodeling. Additionally, the prophylactic administration of FLX, PER, or FLX+PER had no significant effects on serial systolic blood pressure values over the 6 week study. Histological analyses on cardiac tissues samples confirmed significant disruption of myofibrils, vacuolization, and loss of sarcomere integrity in the RC+DOX+TRZ treated mice. Prophylactic administration of FLX or FLX+PER was markedly cardioprotective in preserving myofibril integrity at week 6 in mice receiving the combination therapy of DOX+TRZ. Oxylipin analysis revealed significantly elevated concentrations of inflammatory oxylipins including PGE2 and PGD2 in RC+DOX+TRZ treated mice. Prophylactic administration with FLX, PER, or FLX+PER was able to prevent elevations in inflammatory oxylipins. Finally, western blotting analysis revealed a significant increase in the expression of NF-κβ in RC+DOX+TRZ treated mice. However, pretreatment with FLX, PER, or FLX+PER attenuated elevations in this inflammatory biomarker. Conclusion: In a chronic in vivo female murine model of DOX+TRZ-induced cardiotoxicity, although FLX was equivalent to PER in the prevention of adverse LV remodelling, the combination of FLX and PER was not synergistic.
Cardiotoxicity, Chemotherapy, Doxorubicin, Trastuzumab, Perindopril, Flaxseed