Comparing Flaxseed and Perindopril in the Prevention of Doxorubicin and Trastuzumab-Induced Cardiotoxicity in C57Bl/6 Mice

Abstract

Background: Two anti-cancer agents, doxorubicin (DOX) and trastuzumab (TRZ), are commonly used in the management of breast cancer in women. Despite their efficacy in reducing the morbidity and mortality of individuals with breast cancer, the use of these agents is limited by adverse cardiotoxic side effects. Both the nutraceutical agent flaxseed (FLX) and the pharmaceutical drug perindopril (PER) have been studied individually in the prevention of chemotherapy-mediated cardiac dysfunction. The objective of this study was to determine whether the prophylactic administration of FLX is comparable and/or synergistic with PER in preventing DOX + TRZ-induced cardiotoxicity. Methods: Over a six-week period, 81 wild-type C57Bl/6 female mice (8–12 weeks old) were randomized to receive regular chow (RC) or 10% FLX-supplemented diets with or without PER (3 mg/kg/week; oral gavage). Starting at week 4, mice were randomized to receive a weekly injection of saline or DOX (8 mg/kg) + TRZ (3 mg/kg). Serial echocardiography was conducted weekly and histological and biochemical analyses were performed at the end of the study. Results: In mice treated with RC + DOX + TRZ, left ventricular ejection (LVEF) decreased from 75 ± 2% at baseline to 37 ± 3% at week 6. However, prophylactic treatment with either FLX, PER, or FLX + PER partially preserved left ventricular systolic function with LVEF values of 61 ± 2%, 62 ± 2%, and 64 ± 2%, respectively. The administration of FLX, PER, or FLX + PER was also partially cardioprotective in preserving cardiomyocyte integrity and attenuating the expression of the inflammatory biomarker NF-κB due to DOX + TRZ administration. Conclusion: FLX was equivalent to PER at preventing DOX + TRZ-induced cardiotoxicity in a chronic in vivo murine model.

Efficacy of Flaxseed Compared to ACE Inhibition in Treating Anthracycline- and Trastuzumab-Induced Cardiotoxicity

“… 36 , 38 , 47 Recently, we demonstrated that the prophylactic administration of FLX and PER were equivalent in attenuating DOX + TRZ–induced loss of cellular integrity, myofibril disarray, and vacuolization. 21 To corroborate these findings, the current study revealed significant improvement of DOX + TRZ–induced myocyte damage in all 3 experimental groups, using treatment with PER, FLX, or FLX + PER. This result demonstrates that the histopathologic changes of DOX + TRZ–mediated cardiac injury can be reversed.…”

“… 25 , 36 , 37 , 38 Additionally, we recently demonstrated that the nutraceutical FLX is partially cardioprotective in a chronic in vivo female murine model of DOX + TRX–mediated cardiotoxicity, and it offers equal cardioprotection to an ACEi when used in the prophylactic setting. 20 , 21 In the current chronic in vivo study of established DOX + TRZ–mediated cardiotoxicity, we observed that intervening with either FLX, PER, or FLX + PER improved LV remodeling on both a structural and functional level, with an ∼18% decrease in LVEDD and an ∼40% increase in LVEF, compared to the levels in the control group. As the first murine study to demonstrate the equivalence of FLX and the ACEi PER in the treatment of DOX + TRZ–mediated cardiotoxicity, this raises the question of whether nutraceuticals can be used in lieu of and/or in combination with pharmaceuticals for the management of CTRCD in the clinical setting.…”

“…Promising agents include ACEi and/or angiotensin receptor blockers, β-blockers, statins, antioxidants, and nutraceuticals. 16 , 17 , 20 , 21 , 26 Previous murine studies have demonstrated the efficacy of ACEi in both the prevention and treatment of DOX + TRZ–mediated cardiotoxicity in the in vivo setting. 25 , 36 , 37 , 38 Additionally, we recently demonstrated that the nutraceutical FLX is partially cardioprotective in a chronic in vivo female murine model of DOX + TRX–mediated cardiotoxicity, and it offers equal cardioprotection to an ACEi when used in the prophylactic setting.…”

“…At the study endpoint, plasma samples were collected for oxylipin analysis in a subset of mice, as previously described. 21 Blood samples were collected into ethylenediaminetetraacetic acid–coated blood-collection tubes (Microvette CB 300 K2E, 16.444.100, Sarstedt, Numbrecht, Germany) and centrifuged for 5 minutes at 4°C and 2000 g. The resulting plasma then was stored at -80°C until processing. A total of 97 oxylipins were extracted from prepared plasma samples using Strata-X SPE solid-phase extraction columns (Phenomenex, Torrance, CA) and analyzed by high-performance liquid chromatography–electrospray ionization–tandem mass spectroscopy, as previously described.…”

“…We recently demonstrated that prophylactic treatment with FLX, ALA, and SDG was partially cardioprotective in a chronic in vivo female mouse model of DOX + TRZ– mediated cardiotoxicity, and FLX offers equal cardioprotection to the ACEi perindopril (PER) in the preventative setting. 20 , 21 Considering these findings, a reasonable hypothesis is that FLX may be efficacious, in not only the prevention, 20 , 21 but also the treatment of established DOX + TRZ–mediated cardiotoxicity, through its anti-inflammatory and antioxidant properties.…”