Chantal Y Asselin1, Amy Lam1, David Y C Cheung1, Cameron R Eekhoudt1, Antonia Zhu1, Ishika Mittal1, Andrew Mayba1, Zahra Solati1, Andrea Edel1, J Alejandro Austria1, Harold M Aukema2, Amir Ravandi1,3, James Thliveris4, Pawan K Singal1, Grant N Pierce1, Saroj Niraula5, Davinder S Jassal1,3,6. 1. Institute of Cardiovascular Sciences, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Manitoba, Canada. 2. Department of Food and Human Nutritional Sciences, Faculty of Agriculture and Food Sciences, University of Manitoba, Manitoba, Canada. 3. Section of Cardiology, Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Manitoba, Canada. 4. Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Manitoba, Canada. 5. Section of Oncology, Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Manitoba, Canada. 6. Department of Radiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Manitoba, Canada.
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.
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.
Authors: Nesrine Ebrahim; Hajir A Al Saihati; Ola Mostafa; Amira Hassouna; Sameh Abdulsamea; Eman Abd El Aziz M El Gebaly; Nashwa Hassan Abo-Rayah; Dina Sabry; Mohamed El-Sherbiny; Abdelmonem G Madboly; Noha Ibrahim Hussien; Raja El Hasnaoui Saadani; Hasnaa Ali Ebrahim; Omnia A M Badr; Nehal M Elsherbiny; Rabab F Salim Journal: Int J Mol Sci Date: 2022-05-25 Impact factor: 6.208
Authors: Cameron R Eekhoudt; Tessa Bortoluzzi; Sonu S Varghese; David Y C Cheung; Simon Christie; Skyler Eastman; Ishika Mittal; J Alejandro Austria; Harold M Aukema; Amir Ravandi; James Thliveris; Pawan K Singal; Davinder S Jassal Journal: Curr Oncol Date: 2022-04-21 Impact factor: 3.109