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Journal of Advanced Research May 2023The anti-cancer medication doxorubicin (Dox) is largely restricted in clinical usage due to its significant cardiotoxicity. The only medication approved by the FDA for...
INTRODUCTION
The anti-cancer medication doxorubicin (Dox) is largely restricted in clinical usage due to its significant cardiotoxicity. The only medication approved by the FDA for Dox-induced cardiotoxicity is dexrazoxane, while it may reduce the sensitivity of cancer cells to chemotherapy and is restricted for use. There is an urgent need for the development of safe and effective medicines to alleviate Dox-induced cardiotoxicity.
OBJECTIVES
The objective of this study was to determine whether Paeonol (Pae) has the ability to protect against Dox-induced cardiotoxicity and if so, what are the underlying mechanisms involved.
METHODS
Sprague-Dawley rats and primary cardiomyocytes were used to create Dox-induced cardiotoxicity models. Pae's effects on myocardial damage, mitochondrial function, mitochondrial dynamics and signaling pathways were studied using a range of experimental methods.
RESULTS
Pae enhanced Mfn2-mediated mitochondrial fusion, restored mitochondrial function and cardiac performance both in vivo and in vitro under the Dox conditions. The protective properties of Pae were blunted when Mfn2 was knocked down or knocked out in Dox-induced cardiomyocytes and hearts respectively. Mechanistically, Pae promoted Mfn2-mediated mitochondria fusion by activating the transcription factor Stat3, which bound to the Mfn2 promoter in a direct manner and up-regulated its transcriptional expression. Furthermore, molecular docking, surface plasmon resonance and co-immunoprecipitation studies showed that Pae's direct target was PKCε, which interacted with Stat3 and enabled its phosphorylation and activation. Pae-induced Stat3 phosphorylation and Mfn2-mediated mitochondrial fusion were inhibited when PKCε was knocked down. Furthermore, Pae did not interfere with Dox's antitumor efficacy in several tumor cells.
CONCLUSION
Pae protects the heart against Dox-induced damage by stimulating mitochondrial fusion via the PKCε-Stat3-Mfn2 pathway, indicating that Pae might be a promising therapeutic therapy for Dox-induced cardiotoxicity while maintaining Dox's anticancer activity.
Topics: Rats; Animals; Cardiotoxicity; Mitochondrial Dynamics; Molecular Docking Simulation; Rats, Sprague-Dawley; Doxorubicin; Myocytes, Cardiac; Hydrolases
PubMed: 35842187
DOI: 10.1016/j.jare.2022.07.002 -
Redox Biology Apr 2024Due to the cardiotoxicity of doxorubicin (DOX), its clinical application is limited. Lipid peroxidation caused by excessive ferrous iron is believed to be a key...
Due to the cardiotoxicity of doxorubicin (DOX), its clinical application is limited. Lipid peroxidation caused by excessive ferrous iron is believed to be a key molecular mechanism of DOX-induced cardiomyopathy (DIC). Dexrazoxane (DXZ), an iron chelator, is the only drug approved by the FDA for reducing DIC, but it has many side effects and cannot be used as a preventive drug in clinical practice. Single-nucleus RNA sequencing (snRNA-seq) analysis identified myocardial and epithelial cells that are susceptible to DOX-induced ferroptosis. The glutathione peroxidase 4 (GPX4) activator selenomethione (SeMet) significantly reduced polyunsaturated fatty acids (PUFAs) and oxidized lipid levels in vitro. Consistently, SeMet significantly decreased DOX-induced lipid peroxidation in H9C2 cells and mortality in C57BL/6 mice compared to DXZ, ferrostatin-1, and normal saline. SeMet can effectively reduce serum markers of cardiac injury in C57BL/6 mice and breast cancer patients. Depletion of the GPX4 gene in C57BL/6 mice resulted in an increase in polyunsaturated fatty acid (PUFA) levels and eliminated the protective effect of SeMet against DIC. Notably, SeMet exerted antitumor effects on breast cancer models with DOX while providing cardiac protection for the same animal without detectable toxicities. These findings suggest that pharmacological activation of GPX4 is a valuable and promising strategy for preventing the cardiotoxicity of doxorubicin.
Topics: Humans; Mice; Animals; Female; Phospholipid Hydroperoxide Glutathione Peroxidase; Cardiotoxicity; Mice, Inbred C57BL; Cardiomyopathies; Doxorubicin; Fatty Acids, Unsaturated; Breast Neoplasms
PubMed: 38232458
DOI: 10.1016/j.redox.2023.103024 -
Frontiers in Cardiovascular Medicine 2022Anthracyclines remain an essential component of the treatment of many hematologic and solid organ malignancies, but has important implications on cardiovascular disease.... (Review)
Review
Anthracyclines remain an essential component of the treatment of many hematologic and solid organ malignancies, but has important implications on cardiovascular disease. Anthracycline induced cardiotoxicity (AIC) ranges from asymptomatic LV dysfunction to highly morbid end- stage heart failure. As cancer survivorship improves, the detection and treatment of AIC becomes more crucial to improve patient outcomes. Current treatment modalities for AIC have been largely extrapolated from treatment of conventional heart failure, but developing effective therapies specific to AIC is an area of growing research interest. This review summarizes the current evidence behind the use of neurohormonal agents, dexrazoxane, and resynchronization therapy in AIC, evaluates the clinical outcomes of advanced therapy and heart transplantation in AIC, and explores future horizons for treatment utilizing gene therapy, stem cell therapy, and mechanism-specific targets.
PubMed: 35528842
DOI: 10.3389/fcvm.2022.863314 -
Cells May 2023Anthracyclines such as doxorubicin are widely used chemotherapy drugs. A common side effect of anthracycline therapy is cardiotoxicity, which can compromise heart... (Review)
Review
Anthracyclines such as doxorubicin are widely used chemotherapy drugs. A common side effect of anthracycline therapy is cardiotoxicity, which can compromise heart function and lead to dilated cardiomyopathy and heart failure. Dexrazoxane and heart failure medications (i.e., beta blockers and drugs targeting the renin-angiotensin system) are prescribed for the primary prevention of cancer therapy-related cardiotoxicity and for the management of cardiac dysfunction and symptoms if they arise during chemotherapy. However, there is a clear need for new therapies to combat the cardiotoxic effects of cancer drugs. Exercise is a cardioprotective stimulus that has recently been shown to improve heart function and prevent functional disability in breast cancer patients undergoing anthracycline chemotherapy. Evidence from preclinical studies supports the use of exercise training to prevent or attenuate the damaging effects of anthracyclines on the cardiovascular system. In this review, we summarise findings from experimental models which provide insight into cellular mechanisms by which exercise may protect the heart from anthracycline-mediated damage, and identify knowledge gaps that require further investigation. Improved understanding of the mechanisms by which exercise protects the heart from anthracyclines may lead to the development of novel therapies to treat cancer therapy-related cardiotoxicity.
Topics: Humans; Cardiotoxicity; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Heart Failure; Topoisomerase II Inhibitors; Neoplasms
PubMed: 37174712
DOI: 10.3390/cells12091312 -
Heart Failure Clinics Jul 2022Targeting cardioprotective strategies to patients at the highest risk for cardiac events can help maximize therapeutic benefits. Dexrazoxane, liposomal formulations,... (Review)
Review
Targeting cardioprotective strategies to patients at the highest risk for cardiac events can help maximize therapeutic benefits. Dexrazoxane, liposomal formulations, continuous infusions, and neurohormonal antagonists may be useful for cardioprotection for anthracycline-treated patients at the highest risk for heart failure. Prevalent cardiovascular disease is a risk factor for cardiac events with many cancer therapies, including anthracyclines, anti-human-epidermal growth factor receptor-2 therapy, radiation, and BCR-Abl tyrosine kinase inhibitors, and may be a risk factor for cardiac events with other therapies. Although evidence for cardioprotective strategies is sparse for nonanthracycline therapies, optimizing cardiac risk factors and prevalent cardiovascular disease may improve outcomes.
Topics: Anthracyclines; Antineoplastic Agents; Cardiovascular Diseases; Heart; Heart Failure; Humans; Risk Factors
PubMed: 35718414
DOI: 10.1016/j.hfc.2022.02.001 -
Biomedicine & Pharmacotherapy =... Sep 2023Doxorubicin, a member of the anthracycline family, is a widely prescribed anticancer chemotherapy drug. Unfortunately, cumulative doses of doxorubicin can cause...
Doxorubicin, a member of the anthracycline family, is a widely prescribed anticancer chemotherapy drug. Unfortunately, cumulative doses of doxorubicin can cause mitochondrial dysfunction, leading to acute or chronic cardiotoxicity. This study demonstrated that Neopetroside-B (NPS-B) protects cardiomyocytes in the presence of doxorubicin. NPS-B improved mitochondrial function in cardiomyocytes by increasing ATP production and oxygen consumption rates. On the other hand, NPS-B negatively influenced cancer cell lines by increasing reactive oxygen species. We analyzed NPS-B-influenced metabolites (VIP > 1.0; AUC>0.7; p < 0.05) and proteins (FC > 2.0) and constructed metabolite-protein enrichment, which showed that NPS-B affected uracil metabolism and NAD-binding proteins (e.g., aldehyde dehydrogenase and glutathione reductase) in cardiomyocytes. However, for the cancer cells, NPS-B decreased the NAD/NADH balance, impairing cell viability. In a xenograft mouse model treated with doxorubicin, NPS-B reduced cardiac fibrosis and improved cardiac function. NPS-B may be a beneficial intervention to reducing doxorubicin-induced cardiotoxicity with anticancer effects.
Topics: Humans; Mice; Animals; Cardiotoxicity; NAD; Doxorubicin; Antibiotics, Antineoplastic; Antineoplastic Agents; Myocytes, Cardiac; Mitochondria
PubMed: 37523986
DOI: 10.1016/j.biopha.2023.115232 -
Current Treatment Options in Oncology Feb 2021Heart failure (HF) is increasingly recognized as the major complication of chemotherapy regimens. Despite the development of modern targeted therapies such as monoclonal... (Review)
Review
Heart failure (HF) is increasingly recognized as the major complication of chemotherapy regimens. Despite the development of modern targeted therapies such as monoclonal antibodies, doxorubicin (DOXO), one of the most cardiotoxic anticancer agents, still remains the treatment of choice for several solid and hematological tumors. The insurgence of cardiotoxicity represents the major limitation to the clinical use of this potent anticancer drug. At the molecular level, cardiac side effects of DOXO have been associated to mitochondrial dysfunction, DNA damage, impairment of iron metabolism, apoptosis, and autophagy dysregulation. On these bases, the antioxidant and iron chelator molecule, dexrazoxane, currently represents the unique FDA-approved cardioprotectant for patients treated with anthracyclines.A less explored area of research concerns the impact of DOXO on cardiac metabolism. Recent metabolomic studies highlight the possibility that cardiac metabolic alterations may critically contribute to the development of DOXO cardiotoxicity. Among these, the impairment of oxidative phosphorylation and the persistent activation of glycolysis, which are commonly observed in response to DOXO treatment, may undermine the ability of cardiomyocytes to meet the energy demand, eventually leading to energetic failure. Moreover, increasing evidence links DOXO cardiotoxicity to imbalanced insulin signaling and to cardiac insulin resistance. Although anti-diabetic drugs, such as empagliflozin and metformin, have shown interesting cardioprotective effects in vitro and in vivo in different models of heart failure, their mechanism of action is unclear, and their use for the treatment of DOXO cardiotoxicity is still unexplored.This review article aims at summarizing current evidence of the metabolic derangements induced by DOXO and at providing speculations on how key players of cardiac metabolism could be pharmacologically targeted to prevent or cure DOXO cardiomyopathy.
Topics: Anthracyclines; Antineoplastic Agents; Autophagy; Biomarkers; Cardiotoxicity; Cell Survival; Disease Susceptibility; Fatty Acids; Glycolysis; Humans; Insulin Resistance; Iron; Myocardium; Myocytes, Cardiac; Neoplasms; Oxidation-Reduction
PubMed: 33547494
DOI: 10.1007/s11864-020-00812-1 -
Cureus Nov 2021Pediatric cancers are a common cause of childhood morbidity. As a result, chemotherapeutic regimens have been designed to target childhood cancers. These medications are... (Review)
Review
Pediatric cancers are a common cause of childhood morbidity. As a result, chemotherapeutic regimens have been designed to target childhood cancers. These medications are necessary to treat pediatric cancers, however, oncology management options are accompanied by multiple negative and potentially fatal adverse effects. Although anthracyclines are the most commonly used chemotherapeutic agents associated with cardiotoxicity, we also explore other chemotherapeutic drugs used in children that can potentially affect the heart. Genetic variations resulting in single nucleotide polymorphism (SNP) have the propensity to modify the cardiotoxic effects of the chemotherapy drugs. The clinical presentation of the cardiac effects can vary from arrhythmias and heart failure to completely asymptomatic. A range of imaging studies and laboratory investigations can protect the heart from severe outcomes. The physiology of the heart and the effect of drugs in children vary vividly from adults; therefore, it is crucial to study the cardiotoxic effect of chemotherapy drugs in the pediatric population. This review highlights the potential contributing factors for cardiotoxicity in the pediatric population and discusses the identification and management options.
PubMed: 34976454
DOI: 10.7759/cureus.19658 -
JAMA Cardiology May 2023Anthracycline-containing regimens are highly effective for diffuse large B-cell lymphoma (DLBCL); however, patients with preexisting heart failure (HF) may be less...
IMPORTANCE
Anthracycline-containing regimens are highly effective for diffuse large B-cell lymphoma (DLBCL); however, patients with preexisting heart failure (HF) may be less likely to receive anthracyclines and may be at higher risk of lymphoma mortality.
OBJECTIVE
To assess the prevalence of preexisting HF in older patients with DLBCL and its association with treatment patterns and outcomes.
DESIGN, SETTING, AND PARTICIPANTS
This longitudinal cohort study used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare registry from 1999 to 2016. The SEER registry is a system of population-based cancer registries, capturing more than 25% of the US population. Linkage to Medicare offers additional information from billing claims. This study included individuals 65 years and older with newly diagnosed DLBCL from 2000 to 2015 with Medicare Part A or B continuously in the year prior to lymphoma diagnosis. Data were analyzed from September 2020 to December 2022.
EXPOSURES
Preexisting HF in the year prior to DLBCL diagnosis ascertained from billing codes required one of the following: (1) 1 primary inpatient discharge diagnosis, (2) 2 outpatient diagnoses, (3) 3 secondary inpatient discharge diagnoses, (4) 3 emergency department diagnoses, or (5) 2 secondary inpatient discharge diagnoses plus 1 outpatient diagnosis.
MAIN OUTCOMES AND MEASURES
The primary outcome was anthracycline-based treatment. The secondary outcomes were (1) cardioprotective medications and (2) cause-specific mortality. The associations between preexisting HF and cancer treatment were estimated using multivariable logistic regression. The associations between preexisting HF and cause-specific mortality were evaluated using cause-specific Cox proportional hazards models with adjustment for comorbidities and cancer treatment.
RESULTS
Of 30 728 included patients with DLBCL, 15 474 (50.4%) were female, and the mean (SD) age was 77.8 (7.2) years. Preexisting HF at lymphoma diagnosis was present in 4266 patients (13.9%). Patients with preexisting HF were less likely to be treated with an anthracycline (odds ratio, 0.55; 95% CI, 0.49-0.61). Among patients with preexisting HF who received an anthracycline, dexrazoxane or liposomal doxorubicin were used in 78 of 1119 patients (7.0%). One-year lymphoma mortality was 41.8% (95% CI, 40.5-43.2) with preexisting HF and 29.6% (95% CI, 29.0%-30.1%) without preexisting HF. Preexisting HF was associated with higher lymphoma mortality in models adjusting for baseline and time-varying treatment factors (hazard ratio, 1.24; 95% CI, 1.18-1.31).
CONCLUSIONS AND RELEVANCE
In this study, preexisting HF in patients with newly diagnosed DLBCL was common and was associated with lower use of anthracyclines and lower use of any chemotherapy. Trials are needed for this high-risk population.
Topics: Humans; Female; Aged; United States; Male; Longitudinal Studies; Medicare; Heart Failure; Lymphoma, Large B-Cell, Diffuse; Anthracyclines; Risk Assessment
PubMed: 36988926
DOI: 10.1001/jamacardio.2023.0303 -
Biomedicine & Pharmacotherapy =... Apr 2022Cardiotoxicity remains the most common reason for failure during drug development. Recently, the zebrafish (Danio rerio) model has emerged for the evaluation of...
Cardiotoxicity remains the most common reason for failure during drug development. Recently, the zebrafish (Danio rerio) model has emerged for the evaluation of drug-dependent cardiotoxicity and for the identification of cardioprotective molecules. However, it remains unknown how closely the zebrafish-based results may be translated to humans. To tackle this issue, we established embryonic zebrafish models of doxorubicin-, adrenaline- and terfenadine-induced cardiotoxicity with unified dosing regimen which eventually enabled head-to-head comparison of the drugs. Subsequently, we determined whether human cardioprotective medications - dexrazoxane, metoprolol, carvedilol and valsartan - are able to manage heart dysfunction in zebrafish. Our results indicated that doxorubicin, adrenaline and terfenadine elicited overt signs of cardiotoxicity in fish, and we further showed that the blockade of the renin-angiotensin system and, to a lesser extent, β-adrenergic system, ameliorated the heart disease in zebrafish. From the drug development standpoint, our work opens the possibility to determine the cardiovascular properties of tested compounds using the rapid and affordable zebrafish model.
Topics: Animals; Cardiomyopathies; Cardiotoxicity; Carvedilol; Doxorubicin; Zebrafish
PubMed: 35158142
DOI: 10.1016/j.biopha.2022.112695