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Current Treatment Options in Oncology Aug 2023As chemotherapy continues to improve the lives of patients with cancer, understanding the effects of these drugs on other organ systems, and the cardiovascular system in... (Review)
Review
As chemotherapy continues to improve the lives of patients with cancer, understanding the effects of these drugs on other organ systems, and the cardiovascular system in particular, has become increasingly important. The effects of chemotherapy on the cardiovascular system are a major determinant of morbidity and mortality in these survivors. Although echocardiography continues to be the most widely used modality for assessing cardiotoxicity, newer imaging modalities and biomarker concentrations may detect subclinical cardiotoxicity earlier. Dexrazoxane continues to be the most effective therapy for preventing anthracycline-induced cardiomyopathy. Neurohormonal modulating drugs have not prevented cardiotoxicity, so their widespread, long-term use for all patients is currently not recommended. Advanced cardiac therapies, including heart transplant, have been successful in cancer survivors with end-stage HF and should be considered for these patients. Research on new targets, especially genetic associations, may produce treatments that help reduce cardiovascular morbidity and mortality.
Topics: Humans; Adolescent; Young Adult; Child; Antineoplastic Agents; Cardiotoxicity; Neoplasms; Heart; Cardiomyopathies; Anthracyclines
PubMed: 37296365
DOI: 10.1007/s11864-023-01100-4 -
Current Problems in Cardiology Mar 2023The treatment for multiple myeloma has advanced significantly over the past few decades. Proteasome inhibitors have become the cornerstone of the treatment of multiple... (Review)
Review
The treatment for multiple myeloma has advanced significantly over the past few decades. Proteasome inhibitors have become the cornerstone of the treatment of multiple myeloma. However, proteasome inhibitors have shown cardiovascular complications such as hypertension, pulmonary hypertension, heart failure, arrhythmias, ischaemic heart disease and thromboembolism. Detection, monitoring and management of proteasome inhibitor-related cardiovascular toxicity are essential to improve clinical outcomes for patients. Proposed mechanisms of proteasome inhibitor-related cardiovascular toxicity are apoptosis, prolonged inhibition of the ubiquitin-proteasome system, accumulation of improperly folded proteins within cardiomyocytes and higher protein phosphatase 2A activity. To better understand the mechanisms underlying cardiotoxicity, further in vitro and in vivo experiments are required to investigate these hypotheses. Combined use of metformin or angiotensin II receptor blockers with the proteasome inhibitor, carfilzomib, showed an emerging role as a prophylactic therapy because they can preserve heart function in multiple myeloma patients. Metformin is expected to be an effective therapeutic intervention for the management of carfilzomib-induced cardiotoxicity. There has been evidence that three compounds, apremilast, rutin, and dexrazoxane, can reverse carfilzomib-induced cardiotoxicity in rats. The future transition from animal experiments to clinical trials is worth waiting for.
Topics: Humans; Rats; Animals; Proteasome Inhibitors; Multiple Myeloma; Cardiotoxicity; Heart Diseases; Heart Failure
PubMed: 36481392
DOI: 10.1016/j.cpcardiol.2022.101536 -
Cell Biology and Toxicology Dec 2023Anthracycline antitumor agents, such as doxorubicin (DOX), are effective in the treatment of solid tumors and hematological malignancies, but anthracycline-induced...
Anthracycline antitumor agents, such as doxorubicin (DOX), are effective in the treatment of solid tumors and hematological malignancies, but anthracycline-induced cardiotoxicity (AIC) limits their application as chemotherapeutics. Dexrazoxane (DEX) has been adopted to prevent AIC. Using a chronic AIC mouse model, we demonstrated that DEX is insufficient to reverse DOX-induced cardiotoxicity. Although therapies targeting autophagy have been explored to prevent AIC, but whether novel autophagy inhibitors could alleviate or prevent AIC in clinically relevant models needs further investigation. Here, we show that genetic ablation of Atg7, a key regulator in the early phase of autophagy, protected mice against AIC. We further demonstrated that SAR405, a novel autophagy inhibitor, attenuated DOX-induced cytotoxicity. Intriguingly, the combination of DEX and SAR405 protected cells against DOX-induced cardiotoxicity in vivo. Using the cardiomyocyte cell lines AC16 and H9c2, we determined that autophagy was initiated during AIC. Our results suggest that inhibition of autophagy at its early phase with SAR405 combined with DEX represents an effective therapeutic strategy to prevent AIC.
Topics: Mice; Animals; Cardiotoxicity; Doxorubicin; Antibiotics, Antineoplastic; Myocytes, Cardiac; Anthracyclines; Autophagy; Apoptosis; Oxidative Stress
PubMed: 37768392
DOI: 10.1007/s10565-023-09831-8 -
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 -
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 -
Current Opinion in Pediatrics Oct 2018We review the cardiotoxic chemotherapeutic agents, the clinical and subclinical presentations and progression of their cardiotoxicity, and the management of the... (Review)
Review
PURPOSE OF REVIEW
We review the cardiotoxic chemotherapeutic agents, the clinical and subclinical presentations and progression of their cardiotoxicity, and the management of the subsequent cardiovascular disease in survivors of childhood cancer. We discuss various preventive measures, especially the cardioprotectant, dexrazoxane, whose use with anthracycline chemotherapy, including doxorubicin, is based on strong evidence. Most treatment recommendations for this unique population are based on expert opinion, not on empirical evidence.
RECENT FINDINGS
As patients with childhood cancers live longer, morbidity from the cardiac side effects of chemotherapy is increasing. Treatment-related cardiac damage is irreversible and often progressive. It is imperative that such damage be prevented with strategies such as limiting the cumulative anthracycline dose, the use of anthracycline structural analogues and the use of cardioprotective agents.
SUMMARY
A deeper understanding of the mechanisms of their cardiotoxicity reveals that there is no 'safe' dose of anthracyclines. However, certain risk factors, such as higher lifetime anthracycline cumulative doses, higher anthracycline dose rates, female sex, longer follow-up, younger age at anthracycline treatment and cardiac irradiation, are associated with more severe cardiotoxicity. We advocate the use of dexrazoxane to limit the cardiotoxic effects of anthracycline chemotherapy.
Topics: Adult Survivors of Child Adverse Events; Anthracyclines; Antineoplastic Agents; Cancer Survivors; Cardiotonic Agents; Cardiotoxicity; Cardiovascular Diseases; Dexrazoxane; Humans
PubMed: 30124579
DOI: 10.1097/MOP.0000000000000675 -
Current Oncology Reports Jun 2020Multiple myeloma is the second most common hematologic malignancy in the USA, with over 32,000 new cases and nearly 13,000 deaths expected in 2019. The past few decades... (Review)
Review
PURPOSE OF REVIEW
Multiple myeloma is the second most common hematologic malignancy in the USA, with over 32,000 new cases and nearly 13,000 deaths expected in 2019. The past few decades in myeloma research have yielded significant advances, leading to the expansion of novel anti-myeloma agents. This review describes the incidence and mechanisms of cardiotoxicity for the FDA-approved proteasome inhibitors in myeloma and proposes strategies to assess and manage resultant cardiovascular adverse events.
RECENT FINDINGS
Proteasome inhibition precipitates protein aggregation and alters transcriptional activation of NF-κB targets which contributes to a pro-apoptotic signaling cascade in myeloma cells. Similar effects in cardiomyocytes and vascular smooth muscle endothelium, along with off-target downregulation of autophagy and signaling alterations of nitric oxide homeostasis, may be linked to observed cardiotoxic effects. There is preliminary evidence for cardioprotective potential for rutin, dexrazoxane, and apremilast that could have clinical applicability in the future. Of the proteasome inhibitors used in clinical practice, carfilzomib is the most strongly associated with cardiotoxicity. Patients with anticipated carfilzomib treatment should undergo assessment and optimization of baseline cardiovascular risk, with close monitoring during treatment. Previous clinical trials were not specifically designed to assess proteasome inhibitor-related cardiotoxicity, creating a need for future studies to identify and risk stratify vulnerable individuals and to develop potential cardioprotective strategies in attenuating cardiac injury.
Topics: Cardiotoxicity; Clinical Trials as Topic; Early Diagnosis; Humans; Multiple Myeloma; Proteasome Inhibitors
PubMed: 32514632
DOI: 10.1007/s11912-020-00931-w -
JAMA Network Open Jan 2024Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but... (Clinical Trial)
Clinical Trial
IMPORTANCE
Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but also increased the cumulative doxorubicin dose, making overall treatment consequences for late cardiac toxic effects uncertain.
OBJECTIVE
To estimate the risk of cardiac toxic effects associated with treatments used in modern pediatric HL clinical trials.
DESIGN, SETTING, AND PARTICIPANTS
For this cohort study, Fine and Gray models were fitted using survivors in the Childhood Cancer Survivor Study who were diagnosed with HL between January 1, 1970, and December 31, 1999, and were followed for a median of 23.5 (range, 5.0-46.3) years. These models were applied to the exposures in the study population to estimate the 30-year cumulative incidence of cardiac disease. The study population comprised patients with intermediate-risk or high-risk HL treated in 4 consecutive Children's Oncology Group clinical trials from September 2002 to October 2022: AHOD0031, AHOD0831, AHOD1331, and S1826. Data analysis was performed from April 2020 to February 2023.
EXPOSURES
All patients received chemotherapy including doxorubicin, and some patients received mediastinal RT, dexrazoxane, or mediastinal RT and dexrazoxane.
MAIN OUTCOMES AND MEASURES
Estimated 30-year cumulative incidence of grade 3 to 5 cardiac disease.
RESULTS
The study cohort comprised 2563 patients, with a median age at diagnosis of 15 (range, 1-22) years. More than half of the patients were male (1357 [52.9%]). All 2563 patients received doxorubicin, 1362 patients (53.1%) received mediastinal RT, and 307 patients (12.0%) received dexrazoxane. Radiation therapy use and the median mean heart dose among patients receiving RT decreased, whereas the planned cumulative dose of doxorubicin and use of dexrazoxane cardioprotection increased. For patients treated at age 15 years, the estimated 30-year cumulative incidence of severe or fatal cardiac disease was 9.6% (95% CI, 4.2%-16.4%) in the AHOD0031 standard treatment group (enrolled 2002-2009), 8.6% (95% CI, 3.8%-14.9%) in the AHOD0831 trial (enrolled 2009-2012), 8.2% (95% CI, 3.6%-14.3%) in the AHOD1331 trial (enrolled 2015-2019), and 6.2% (95% CI, 2.7%-10.9%) in the S1826 trial (enrolled 2019-2022), whereas the expected rate in an untreated population was 5.0% (95% CI, 2.1%-9.3%). Despite the estimated reduction in late cardiac morbidity, the frequency of recommended echocardiographic screening among survivors will increase based on current guidelines.
CONCLUSIONS AND RELEVANCE
In this cohort study of sequential HL trials, reductions in the proportion of children receiving mediastinal RT and increases in dexrazoxane use were estimated to offset the increased doxorubicin dose and produce a net reduction in late cardiac disease. Further studies on dexrazoxane are warranted to confirm whether its role in reducing cardiac toxic effects is maintained long term. These findings suggest that survivorship follow-up guidelines should be refined to align with the risks associated with treatment.
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Infant; Male; Young Adult; Cardiotoxicity; Clinical Protocols; Cohort Studies; Dexrazoxane; Doxorubicin; Heart Diseases; Hodgkin Disease
PubMed: 38241048
DOI: 10.1001/jamanetworkopen.2023.51062 -
Revista Portuguesa de Cardiologia :... Jun 2016The increasing use of anthracyclines, together with the longer survival of cancer patients, means the toxic effects of these drugs need to be monitored. In order to... (Review)
Review
The increasing use of anthracyclines, together with the longer survival of cancer patients, means the toxic effects of these drugs need to be monitored. In order to detect, prevent or mitigate anthracycline-induced cardiomyopathy, it is essential that all patients undergo a rigorous initial cardiovascular assessment, followed by close monitoring. Several clinical trials have shown the cardioprotective effect of non-pharmacological measures such as exercise, healthy lifestyles, control of risk factors and treatment of comorbidities; a cardioprotective effect has also been observed with pharmacological measures such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, statins, dexrazoxane and liposomal formulations. However, there are currently no guidelines for managing prevention in these patients. In this review the authors discuss the state of the art of the assessment, monitoring, and, above all, the prevention of anthracycline-induced cardiotoxicity.
Topics: Anthracyclines; Antineoplastic Agents; Cardiomyopathies; Cardiotoxicity; Humans; Neoplasms
PubMed: 27255173
DOI: 10.1016/j.repc.2015.12.004 -
Mini Reviews in Medicinal Chemistry 2017The anthracycline doxorubicin (DOX) has proved to be one of the most widely used and most effective antitumor drugs since its emergence in the 1960s. However, the... (Review)
Review
INTRODUCTION
The anthracycline doxorubicin (DOX) has proved to be one of the most widely used and most effective antitumor drugs since its emergence in the 1960s. However, the utility of DOX is compromised by its potential lethal cardiotoxicity. In this review we summarize development in prevention and management of DOX-induced cardiotoxicity comprehensively.
BACKGROUND
Strategies to enhance DOX efficacy in cancer cells while minimizing associated cardiotoxicity may prove clinically valuable. Employment of DOX derivatives, including currently available mitoxantrone and epirubicin, has been testified in several clinical trials. Several cardioprotective agents, including dexrazoxane, statins, angiotensin-converting enzyme inhibitors, calcium channel blockers, beta-blockers, and etc., have been developed and tested in animal and clinical trials.
CONCLUSION
Several strategies have been reported on the prevention and management of DOX-elicited cardiotoxicity, and many of them await verification from large scale clinical trials. Dexrazoxane has been approved to prevent and treat side effects of DOX, although concerns still exist that it might increase incidence of some kind of malignant tumors. Promising findings in autophagy, RNA binding protein quaking and statins encourage further research developing strategies by which heart protection and cancer cell killing are achieved simutaneously.
Topics: Antibiotics, Antineoplastic; Cardiotonic Agents; Cardiotoxicity; Doxorubicin; Humans; Neoplasms
PubMed: 27337969
DOI: 10.2174/1389557516666160621083659