Little is known about whether flaxseed (FLX) is equivalent or synergistic with angiotensin-converting enzyme (ACEi) inhibition in the treatment of DOX+TRZ-induced cardiotoxicity. Treatment with FLX, PER, or FLX+PER, however, improved myofibril integrity at week 6 in DOX+TRZ-treated mice.
Introduction
Breast Cancer
- Epidemiology
- Risk Factors
- Diagnosis
- Treatment
Surgical interventions to treat breast cancer were the first major step in improving patient survival. TRZ is the most commonly used monoclonal antibody in both adjuvant and metastatic breast cancer settings to improve patient survival and reduce the risk of relapse and is a standard component of the treatment of HER2 positive breast cancer.25-28.
Cardio-Oncology
- Chemotherapy & Targeted Biological Therapy
- Cancer Therapy Related Cardiac Dysfunction
- Cardiovascular Imaging
- Biomarkers
- Prevention & Treatment of Chemotherapy Mediated Cardiotoxicity
Anthracyclines, such as DOX and EPR, are the main culprit in the development of chemotherapy-mediated cardiotoxicity. The MANTICORE study, which focused exclusively on preventing TRZ-mediated cardiotoxicity type II, showed that the ACEi PER and the b-blocker bisoprolol were effective in preventing a decrease in LVEF.81.
Nutraceuticals
- Flaxseed
- Cancer
- Cardiovascular Disease
- Flaxseed in the Prevention of Chemotherapy Mediated Cardiotoxicity
The effects of dietary FLX consumption on cancer have been investigated in both pre-clinical and clinical trials, showing a protective effect, particularly in the breast cancer setting.169-171 FLX supplementation can reduce both cancer risk and disease progression.169,170 In pre Clinical models, SDG and FLX have been shown to support the treatment of cancer by reducing estrogen activity and enhancing TRZ efficacy, respectively.172,173 In the high-estrogen environment of breast cancer, dietary SDG has a SERM-like anti-estrogenic effect that normalize dysplasia, cell number, and. The effectiveness of FLX in reducing breast cancer risk has also been established in clinical studies.174,175 A comparative study showed an association between FLX intake and a reduction in breast cancer risk suggesting a potential role in breast cancer prevention.174 A randomized, double-blind, placebo-controlled, prospective study found that 30 days of dietary FLX consumption in postmenopausal women with primary breast cancer increased tumor cell proliferation, increased tumor apoptosis, and increased urinary lignan excretion, suggesting that FLX has the potential to inhibit tumor growth in patients with breast cancer.175 Further clinical studies have shown that FLX consumption does not interfere with the cytotoxic abilities of anti-cancer treatments, and may in fact enhance specific anti-cancer agents such as TRZ. Up to 30% of breast cancer patients consume FLX due to the possibility of reducing cancer progression and preventing co-morbidities, without the side effects associated with pharmaceutical products.167,174 Therefore, FLX consumption is safe and effective in the breast cancer setting and can has a double advantage. The effects of dietary FLX consumption on cardiovascular diseases have also been investigated in pre-clinical trials, clinical trials and systematic reviews showing a positive effect in the pathological cascades of atherosclerosis, hypertension, arrhythmias and heart failure.
In pre-clinical trials, mouse models have demonstrated that FLX has anti-atherosclerotic effects, demonstrating both plaque prevention and plaque regression in the presence of high-cholesterol or high-fat diets. 185-189 A murine model of myocardial infarction (MI) demonstrated that FLX also reduces The FlaxPAD study was a prospective, double-blind, placebo-controlled, randomized clinical trial which found that FLX significantly reduced both systolic and diastolic blood pressure in patients with peripheral artery disease showing the most potent antihypertensive effect ever achieved through dietary intervention.191 Further analysis of the FlaxPAD population found that FLX also significantly lowers central aortic systolic and diastolic blood pressure in hypertensive patients.192 The antihypertensive effects of FLX have been confirmed by several other clinical trials and meta- analysis.193-199 Another double-blind, placebo-controlled, randomized clinical trial found that dietary FLX can lower plasma cholesterol and glucose concentrations in a dose-dependent manner, further supporting the role of FLX in the treatment of vascular disease.200 Looking specifically at ALA, reviews have concluded that ALA can be used to reduce heart rate (HR) or as a form of clinical prevention for sudden cardiac death, due of its anti-arrhythmic effects.201 In general, there is considerable support for the clinical use of dietary FLX in the treatment of cardiovascular diseases due to its high content of ALA and SDG that contribute to anti-atherosclerotic, anti-arrhythmic effects and antihypertensives, all of which are effective components in the treatment of heart failure. 202-204 The existing evidence about the health benefits of FLX in a variety of cardiovascular diseases supports further investigation into the potential clinical uses of FLX in other cardiovascular disease contexts. Previous trials have shown the efficacy of prophylactic FLX in preventing chemotherapy-mediated cardiotoxicity.
Considering these findings, in addition to the previously described effect of dietary FLX in the treatment of atherosclerosis, arrhythmias, hypertension and sudden cardiac death, it is reasonable to hypothesize that FLX may be effective in the treatment of chemotherapy-mediated cardiotoxicity. Little is known about the effects of FLX in the context of Cardio-Oncology, which supports investigation into the role of FLX in the treatment setting.
Rationale, Hypothesis, & Objectives
Rationale
Hypothesis
Objectives
Methods
- Animal Model
- Murine Echocardiography
- Histology
- Hemodynamics
- Western Blot Analyses
- Oxylipins
- Statistical Analysis
Digital images were then taken with a Philips CM12 electron microscope to determine the degree of cellular integrity. LV tissue samples were snap-frozen in liquid nitrogen, then pressed and homogenized in a radioimmunoprecipitation assay (RIPA) lysis buffer containing phosphatase inhibitor (Product #: . A32957, Thermo Scientific) and protease inhibitor (Product # : A32965 total scientific isol) cellular proteins by preventing protein degradation. After a 30-min incubation period on ice, samples were centrifuged to remove cellular debris and supernatants were collected.
Samples were run on a 5% run and an 8%, 10%, or 12% resolving sodium dodecyl sulfate (SDS) polyacrylamide gel. Proteins were then transferred to a polyvinylidene difluoride (PVDF) membrane with a pore size of 0.2 μm (Product #: 88520, Thermo Scientific) for 60 min at 100V and 7°C. After being on ice for 15 minutes, samples were centrifuged for 5 minutes at 4°C and 2000 g to remove blood cells, then plasma was dispensed into sterile 1.5mL plasma tubes and stored at -80°C until processing. .
After mixing, the samples were tested using pH indicator strips and then adjusted to pH 3.0 if necessary, using 1N hydrogen chloride (HCl) and 1N sodium hydroxide (NaOH). The samples were then dried under N2 set to gently blow on the surface of the samples in an evaporator at 37°C for 60 to 90 minutes.
Results
- Murine Echocardiography
- Histology
- Hemodynamics
- Western Blot Analyses
- Oxylipins
Treatment with FLX, PER or FLX+PER reduced these histopathological changes (Figures 11C-11E) compared to treatment with DOX+TRZ (p<0.05). In mice treated with DOX+TRZ there was a 2.3-fold increase in HMGB1 expression compared to healthy control mice (p<0.05) (Figure 13). Increases in this necrosis biomarker were significantly downregulated in mice treated with FLX, PER, or FLX+PER (p<0.05).
In mice treated with DOX+TRZ there was a 2.4-fold increase in Bnip-3 expression compared to healthy control mice (p<0.05) (Figure 14). Increases in this mitochondrial biomarker were significantly downregulated in mice treated with FLX, PER, or FLX+PER (p<0.05). In mice treated with DOX+TRZ there was a 3.3-fold increase in net calculated 18-HETE concentration compared to healthy control mice (p<0.05) (Figure 15).
Elevations of this oxylipin were significantly reduced in mice treated with FLX, PER or FLX+PER (p<0.05). There was a 7.3-fold increase in net calculated 20-COOH-AA concentration in DOX+TRZ-treated mice compared to healthy control mice (p<0.05) (Figure 16).
Discussion
- Reversal of Adverse Cardiovascular Remodelling
- Histological Overview of Cardiotoxicity
- Mechanistic Pathways of Cardiotoxicity
- Mitochondrial Induced Ferroptosis
- Mitochondrial Induced Apoptosis & Necrosis
- Inflammatory Changes in Cardiotoxicity
- Limitations
- Future Directions & Clinical Implications
In the clinical environment, both RAS antagonists and b-blockers are first-line agents in the treatment of DOX+TRZ-mediated cardiotoxicity.107 In 2002, Jensen et al wrote. In the current chronic in vivo study, we assessed whether FLX, PER or the combination can be used in the treatment of established DOX+TRZ-mediated cardiotoxicity. This is the first study to demonstrate the equivalence of FLX compared to the ACEi PER in the treatment of DOX+TRZ-mediated cardiotoxicity in a murine model.
The intermediate levels of cellular damage in the three experimental groups suggest that FLX and PER are both effective in partially attenuating DOX+TRZ-mediated cardiotoxicity. In the present study, HMGB1 expression was increased in the DOX+TRZ group, demonstrating that oxidative stress induced ferroptosis. It is likely that DOX+TRZ induced the accumulation of iron ions in mitochondria, driving cardiomyocytes toward ferroptosis.
In the present study, we demonstrated that Bnip-3 expression was increased by 2.3-fold in DOX + TRZ-treated mice. To fully translate the role of FLX+PER in the clinical treatment of DOX+TRX-mediated cardiotoxicity, further investigations are required.
Conclusions
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Flaxseed inhibits metastasis and reduces extracellular vascular endothelial growth factor in human breast cancer xenografts.
