Abstract
Background: Although the combination of doxorubicin (DOX) and trastuzumab (TRZ) reduces the progression and recurrence of breast cancer, these anticancer drugs are associated with significant cardiotoxic side effects. Objective: We investigated whether prophylactic administration of flaxseed (FLX) and its bioactive components, α-linolenic acid (ALA) and secoisolariciresinol diglucoside (SDG), would be cardioprotective against DOX + TRZ–mediated cardiotoxicity in a chronic in vivo female murine model. Methods: Wild-type C57BL/6 female mice (10–12 wk old) received daily prophylactic treatment with one of the following diets: 1) regular control (RC) semi-purified diet; 2) 10% FLX diet; 3) 4.4% ALA diet; or 4) 0.44% SDG diet for a total of 6 wks. Within each arm, mice received 3 weekly injections of 0.9% saline or a combination of DOX [8 mg/(kg.wk)] and TRZ [3 mg/(kg.wk)] starting at the end of week 3. The main outcome was to evaluate the effects of FLX, ALA, and SDG on cardiovascular remodeling and markers of apoptosis, inflammation, and mitochondrial dysfunction. Significance between measurements was determined using a 4 (diet) × 2 (chemotherapy) × 2 (time) mixed factorial design with repeated measures. Results: In the RC + DOX + TRZ–treated mice at week 6 of the study, the left ventricular ejection fraction (LVEF) decreased by 50% compared with the baseline LVEF (P < 0.05). However, the prophylactic administration of the FLX, ALA, or SDG diet was partially cardioprotective, with mice in these treatment groups showing an ∼68% increase in LVEF compared with the RC + DOX + TRZ–treated group at week 6 (P < 0.05). Although markers of inflammation (nuclear transcription factor κB), apoptosis [poly (ADP-ribose) polymerase–1 and the ratio of BCL2-associated X protein to B-cell lymphoma–extra large], and mitochondrial dysfunction (BCL2-interacting protein 3) were significantly elevated by approximately 2-fold following treatment with RC + DOX + TRZ compared with treatment with RC + saline at week 6, prophylactic administration of FLX, ALA, or SDG partially downregulated these signaling pathways. Conclusion: In a chronic in vivo female C57BL/6 mouse model of DOX + TRZ–mediated cardiotoxicity, FLX, ALA, and SDG were partially cardioprotective.
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Key Points
Doxorubicin (DOX) is an anthracycline that is commonly used to treat women with breast cancer in both the adjuvant and metastatic settings. Trastuzumab (TRZ), a monoclonal antibody specific to the human epidermal growth factor receptor 2, potentiates the anticancer activity of DOX. Among the potential mechanisms of DOX + TRZ–mediated cardiotoxicity, there has been an increased focus on the roles of inflammation and oxidative stress (OS), which lead to myocardial fibrosis, apoptosis, and heart failure. DOX elicits inflammatory effects on the myocardium and vasculature by increasing the activation of redox-sensitive transcription factors, specifically nuclear transcription factor κB (NFKB), thereby upregulating the downstream production of proinflammatory mediators, including tumor necrosis factor α, IL-1β, and IL-6.
Flaxseed (FLX) is rich in both α-linolenic acid (ALA) and the lignan secoisolariciresinol diglucoside (SDG) have potent anti-inflammatory and antioxidative properties, respectively. Prophylactic treatment with ALA in rats receiving DOX was partially cardioprotective, with an improvement in left-ventricular remodeling and attenuation of OS and apoptosis, Dietary supplementation with FLX oil over a 4-wk period enhanced the tumor-reducing effects of TRZ in an in vivo murine model. The objective of the current study is to evaluate whether prophylactic administration of FLX, or its bioactive components ALA and SDG, will prevent DOX + TRZ–mediated cardiac dysfunction in a chronic in vivo female murine model of chemotherapy induced cardiotoxicity.
This study demonstrated for the first time that the prophylactic treatment with FLX, and its constituents ALA and SDG, significantly attenuated the cardiotoxic side effects of DOX + TRZ in a chronic in vivo female murine model of chemotherapy-induced cardiomyopathy. Specifically, FLX does the following: 1) prevents adverse left ventricular remodeling due to DOX + TRZ; 2) mitigates myofibrillar disarray; 3) reduces the degree of inflammation following treatment with DOX + TRZ; and 4) attenuates the degree of cardiac apoptosis, oxidative stress, and mitochondrial dysfunction. The study demonstrated that the prophylactic administration of FLX, ALA, and SDG partially attenuated DOX + TRZ–mediated cardiotoxicity in a chronic in vivo female murine model. Future clinical studies are warranted to investigate the prophylactic role of FLX consumption in preventing the cardiotoxic side effects of DOX + TRZ in breast cancer.