Is flaxseed equivalent and/or synergistic with ACE inhibition in the treatment of chemotherapy induced cardiotoxicity?
| dc.contributor.author | Telles-Langdon, Sara | |
| dc.contributor.examiningcommittee | Dixon, Ian (Physiology and Pathophysiology) | en_US |
| dc.contributor.examiningcommittee | Ravandi, Amir (Internal Medicine) | en_US |
| dc.contributor.examiningcommittee | Wigle, Jeffrey (Biochemistry and Medical Genetics) | en_US |
| dc.contributor.supervisor | Jassal, Davinder S. | |
| dc.contributor.supervisor | Singal, Pawan K. | |
| dc.date.accessioned | 2023-04-11T20:24:55Z | |
| dc.date.available | 2023-04-11T20:24:55Z | |
| dc.date.copyright | 2023-03-28 | |
| dc.date.issued | 2023-03-28 | |
| dc.date.submitted | 2023-03-28T19:05:33Z | en_US |
| dc.degree.discipline | Physiology and Pathophysiology | en_US |
| dc.degree.level | Master of Science (M.Sc.) | en_US |
| dc.description.abstract | Background: Breast cancer is a major public health concern in Canada. Although the current combination of surgery, radiation, and chemotherapy may lead to a cure in the breast cancer setting, the administration of the anti-cancer drugs Doxorubicin and Trastuzumab (DOX+TRZ) is associated with an increased risk of developing heart failure. Little is known about whether flaxseed (FLX) is equivalent to, or synergistic with, angiotensin converting enzyme inhibition (ACEi) in the treatment of DOX+TRZ mediated cardiotoxicity. Objective: The specific aim is to evaluate whether FLX is comparable and/or incremental to standard pharmacological therapy using the ACEi Perindopril (PER) in the treatment of DOX+TRZ mediated cardiotoxicity. Methods: In a chronic in vivo murine model of chemotherapy mediated cardiotoxicity, DOX+TRZ (8mg/kg and 3mg/kg, respectively) were administered weekly for a total of 3 weeks. Following this regimen, the mice were randomized to daily consumption of a 10% FLX supplemented diet, administration of PER (3mg/kg) via oral gavage, or a combination of both FLX+PER for an additional 3 weeks. Serial echocardiography was performed weekly. At the end of week 6, the mice were euthanized, and histological and biochemical analyses were performed on cardiac tissue and plasma. Results: In mice treated with DOX+TRZ, the left ventricular ejection fraction (LVEF) decreased from 74±4% at baseline to 39±5% at week 6. Treatment with either FLX, PER, or FLX+PER improved LVEF to 63±4%, 64±3%, and 65±4%, respectively (p<0.05). Histological analyses confirmed significant disruption of myofibrils, vacuolization, and loss of sarcomere integrity in the DOX+TRZ treated mice. Treatment with FLX, PER, or FLX+PER, however, improved myofibril integrity at week 6 in mice receiving DOX+TRZ. Although Bcl-2 interacting protein 3 (Bnip-3) and high mobility group box 1 protein (HMGB1) expression were significantly elevated in mice receiving DOX+TRZ, these markers of mitochondrial damage and cell death were attenuated by treatment with either FLX, PER, or FLX+PER. Finally, oxylipin analysis showed that 18-hydroxy-eicosatetraenoic acid (18-HETE) and 20-carboxy-arachidonic acid (20-COOH-AA) concentrations were significantly elevated in mice receiving DOX+TRZ; increases in concentrations of these oxylipins were attenuated by treatment with either FLX, PER, or FLX+PER. Conclusion: In a chronic in vivo murine model of DOX+TRZ induced cardiotoxicity, FLX was equivalent to PER at improving cardiovascular remodeling, reducing histopathological changes in cardiomyocyte ultrastructure, and reducing biomarkers of inflammation, mitochondrial damage, and cell death in the treatment of cardiotoxicity, but the combination of FLX+PER was not synergistic. | en_US |
| dc.description.note | May 2023 | en_US |
| dc.description.sponsorship | Canadian Institutes of Health Research: 2022 Canada Graduate Scholarships-Master's (CGS M) | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/37271 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Cardio-Oncology | en_US |
| dc.subject | Cardiotoxicity | en_US |
| dc.subject | Nutraceuticals | en_US |
| dc.subject | Flaxseed | en_US |
| dc.subject | Murine model | en_US |
| dc.title | Is flaxseed equivalent and/or synergistic with ACE inhibition in the treatment of chemotherapy induced cardiotoxicity? | en_US |
| dc.type | master thesis | en_US |
| local.subject.manitoba | no | en_US |
| oaire.awardNumber | G-19-0024241 | en_US |
| oaire.awardTitle | Flaxseed in the prevention and treatment of anthracycline and trastuzumab mediated cardiotoxicity | en_US |
| project.funder.identifier | HSFC: http://dx.doi.org/10.13039/100004411 | en_US |
| project.funder.name | Heart and Stroke Foundation of Canada | en_US |