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Journal of the American Heart... May 2024The only clinically approved drug that reduces doxorubicin cardiotoxicity is dexrazoxane, but its application is limited due to the risk of secondary malignancies. So,...
BACKGROUND
The only clinically approved drug that reduces doxorubicin cardiotoxicity is dexrazoxane, but its application is limited due to the risk of secondary malignancies. So, exploring alternative effective molecules to attenuate its cardiotoxicity is crucial. Colchicine is a safe and well-tolerated drug that helps reduce the production of reactive oxygen species. High doses of colchicine have been reported to block the fusion of autophagosomes and lysosomes in cancer cells. However, the impact of colchicine on the autophagy activity within cardiomyocytes remains inadequately elucidated. Recent studies have highlighted the beneficial effects of colchicine on patients with pericarditis, postprocedural atrial fibrillation, and coronary artery disease. It remains ambiguous how colchicine regulates autophagic flux in doxorubicin-induced heart failure.
METHODS AND RESULTS
Doxorubicin was administered to establish models of heart failure both in vivo and in vitro. Prior studies have reported that doxorubicin impeded the breakdown of autophagic vacuoles, resulting in damaged mitochondria and the accumulation of reactive oxygen species. Following the administration of a low dose of colchicine (0.1 mg/kg, daily), significant improvements were observed in heart function (left ventricular ejection fraction: doxorubicin group versus treatment group=43.75%±3.614% versus 57.07%±2.968%, =0.0373). In terms of mechanism, a low dose of colchicine facilitated the degradation of autolysosomes, thereby mitigating doxorubicin-induced cardiotoxicity.
CONCLUSIONS
Our research has shown that a low dose of colchicine is pivotal in restoring the autophagy activity, thereby attenuating the cardiotoxicity induced by doxorubicin. Consequently, colchicine emerges as a promising therapeutic candidate to improve doxorubicin cardiotoxicity.
Topics: Colchicine; Doxorubicin; Cardiotoxicity; Autophagy; Lysosomes; Animals; Myocytes, Cardiac; Disease Models, Animal; Male; Heart Failure; Antibiotics, Antineoplastic; Reactive Oxygen Species; Mice; Mice, Inbred C57BL; Ventricular Function, Left
PubMed: 38700005
DOI: 10.1161/JAHA.123.033700 -
Magyar Onkologia Mar 2011Paravasation of cytostatic drugs during peripheral intravenous administration is a well known complication. In the United States of America it occurs in seven percent of... (Review)
Review
Paravasation of cytostatic drugs during peripheral intravenous administration is a well known complication. In the United States of America it occurs in seven percent of cases with different severity and consequences. Although methods to completely avoid this complication are still unavailable, we are able to decrease the risks by identifying the patient- and procedure-related factors. The educated patient is a good indicator of paravasation in case he or she can cooperate and call the nurse. When the patient is unable to cooperate, the risks of extravasation is higher and closer nursing surveillance is indicated. The extent of injury depends mainly on the chemical structure of the extravasant substance (vesicant, irritant or non-vesicant) which may be modified by other factors. There is no strong evidence-based guidance for the management of complication. Abrupt cessation of the infusion and drawing back on the inserted venous catheter as well as elevating and resting the affected limb are necessary measures. In the available literature cooling or warming of the affected area is controversial. Similarly there are still open questions regarding the value of using antidotes as dexrazoxane, dimethylsulfoxide, thiosulfate and hyaluronidase (which is not registered as medicament in Hungary). In the event of extravasation early multidisciplinary dermatological and surgical assessment is essential for definitive diagnosis and setting the optimal management.
Topics: Antidotes; Antineoplastic Agents; Catheters, Indwelling; Cryotherapy; Cytostatic Agents; Dimethyl Sulfoxide; Extravasation of Diagnostic and Therapeutic Materials; Humans; Hungary; Hyaluronoglucosaminidase; Infusions, Intravenous; Interdisciplinary Communication; Irritants; Razoxane; Risk Factors; Skin; Thiosulfates; United States
PubMed: 21617786
DOI: No ID Found -
Current Heart Failure Reports Jun 2015The success achieved in advances in cancer therapy has been marred by development of cardiotoxicity, which causes significant morbidity and mortality. This has led to... (Review)
Review
The success achieved in advances in cancer therapy has been marred by development of cardiotoxicity, which causes significant morbidity and mortality. This has led to the development of surveillance protocols for cardiotoxicity utilizing multimodality imaging techniques and investigation of various drugs to treat and prevent cardiotoxicity in this subset of patients. Cardiac biomarkers hold important diagnostic and prognostic value in various cardiac diseases. In this review, we discuss the use of biomarkers in patients receiving chemotherapy, highlighting data behind the use of troponin, B-type natriuretic peptide, and myeloperoxidase. We also discuss the use of dexrazoxane, angiotensin-converting enzyme inhibitors, and beta blockers in the treatment and prevention of chemotherapy-induced cardiotoxicity. Cardiac biomarkers may serve an important role in selecting patients that are at high risk of cardiotoxicity and can potentially be used to guide the administration of drugs to treat and prevent cardiotoxicity.
Topics: Antineoplastic Agents; Biomarkers; Heart Diseases; Humans; Natriuretic Peptide, Brain; Peroxidase; Troponin
PubMed: 25869733
DOI: 10.1007/s11897-015-0258-4 -
Antioxidants & Redox Signaling Mar 2013Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron... (Review)
Review
SIGNIFICANCE
Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron transport, synthesis of heme, and as a co-factor for many redox enzymes. Topoisomerases serve as critical enzymes that resolve topological problems during DNA synthesis, transcription, and repair. Neoplastic cells have higher uptake and utilization of iron, as well as elevated levels of topoisomerase family members. Separately, the chelation of iron and the cytotoxic inhibition of topoisomerase have yielded potent anticancer agents.
RECENT ADVANCES
The chemotherapeutic drugs doxorubicin and dexrazoxane both chelate iron and target topoisomerase 2 alpha (top2α). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2α inhibitors. The growing list of agents that appear to chelate iron and inhibit topoisomerases prompts the question of whether and how these two distinct mechanisms might interplay for a cytotoxic chemotherapeutic outcome.
CRITICAL ISSUES
While iron chelation and topoisomerase inhibition each represent mechanistically advantageous anticancer therapeutic strategies, dual targeting agents present an attractive multi-modal opportunity for enhanced anticancer tumor killing and overcoming drug resistance. The commonalities and caveats of dual inhibition are presented in this review.
FUTURE DIRECTIONS
Gaps in knowledge, relevant biomarkers, and strategies for future in vivo studies with dual inhibitors are discussed.
Topics: Antineoplastic Agents; Cardiotonic Agents; DNA Topoisomerases; Humans; Iron; Iron Chelating Agents; Neoplasms; Topoisomerase Inhibitors
PubMed: 22900902
DOI: 10.1089/ars.2012.4877 -
Journal of Medicine and Life Apr 2023Cancer is a major public health problem, and chemotherapy plays a significant role in the management of neoplastic diseases. However, chemotherapy-induced cardiotoxicity... (Review)
Review
Cancer is a major public health problem, and chemotherapy plays a significant role in the management of neoplastic diseases. However, chemotherapy-induced cardiotoxicity is a serious side effect secondary to cardiac damage caused by antineoplastic's direct and indirect toxicity. Currently, there are no reliable and approved methods for preventing or treating chemotherapy-induced cardiotoxicity. Understanding the mechanisms of chemotherapy-induced cardiotoxicity may be vital to improving survival. The independent risk factors for developing cardiotoxicity must be considered to prevent myocardial damage without decreasing the therapeutic efficacy of cancer treatment. This systematic review aimed to identify and analyze the evidence on chemotherapy-induced cardiotoxicity, associated risk factors, and methods to decrease or prevent it. We conducted a comprehensive search on PubMed, Google Scholar, and Directory of Open Access Journals (DOAJ) using the following keywords: "doxorubicin cardiotoxicity", "anthracycline cardiotoxicity", "chemotherapy", "digoxin decrease cardiotoxicity", "ATG7 activators", retrieving 59 articles fulfilling the inclusion criteria. Therapeutic schemes can be changed by choosing prolonged infusion application over boluses. In addition, some agents like Dexrazoxane can reduce chemotherapy-induced cardiotoxicity in high-risk groups. Recent research found that Digoxin, ATG7 activators, Resveratrol, and other medical substances or herbal compounds have a comparable effect on Dexrazoxane in anthracycline-induced cardiotoxicity.
Topics: Humans; Resveratrol; Cardiotoxicity; Dexrazoxane; Anthracyclines; Digoxin; Polyketides; Antineoplastic Agents
PubMed: 37305823
DOI: 10.25122/jml-2022-0322 -
Basic & Clinical Pharmacology &... Oct 2013Cardiotoxicity is one of the main limiting side effects of doxorubicin and cyclophosphamide (DC) treatment, and this study was organized to identify cardioprotective...
Cardiotoxicity is one of the main limiting side effects of doxorubicin and cyclophosphamide (DC) treatment, and this study was organized to identify cardioprotective activity of amifostine and dexrazoxane against DC combination. BalbC/NIH mice underwent DC treatment (DC group), were pre-treated with amifostine (ADC group) or dexrazoxane (IDC group) and were killed at 1.5 and 3 months after treatments when the grade of myocardial damage was analysed by light microscopy using the Billingham scoring method. DC treatment induced severe myocardial damage with one lethal event before evaluation at 3 months. Main characteristics of DC cardiotoxicity were polymorphic myocyte degeneration and alterations in blood vessels followed by ecchymoses, haemorrhage and thromboses. Polymorphism was also found in the IDC and ADC groups, but its morphological patterns were different. In animals subject to IDC treatment, the blood vessels were better preserved than in the ADC group, whereas thrombosis was not seen in either of these two groups. Quantitatively, grade of myocardial injury in the ADC and IDC groups was significantly higher compared with the non-treated group at both times of estimation and significantly lower compared with the DC group at 1.5 months. At 3 months, significance against DC treatment was lost in the ADC group, while preserved in the IDC-treated animals. Also, there was significant progression in the ADC group comparing scores between 1.5 and 3 months. These results revealed that the cardiotoxicity of DC combination displays specific morphological hallmark and evolution in time, different to those described after doxorubicin single treatment. Neither amifostine nor dexrazoxane prevented development of cardiomyopathy induced by DC treatment.
Topics: Amifostine; Animals; Antineoplastic Combined Chemotherapy Protocols; Cardiomyopathies; Cardiotonic Agents; Cyclophosphamide; Dexrazoxane; Doxorubicin; Drug Combinations; Female; Mice; Mice, Inbred BALB C; Myocardium
PubMed: 23692343
DOI: 10.1111/bcpt.12086 -
Oxidative Medicine and Cellular... 2016Despite their recognized cardiotoxic effects, anthracyclines remain an essential component in many anticancer regimens due to their superior antitumor efficacy.... (Review)
Review
Despite their recognized cardiotoxic effects, anthracyclines remain an essential component in many anticancer regimens due to their superior antitumor efficacy. Epidemiologic data revealed that about one-third of cancer patients have hypertension, which is the most common comorbidity in cancer registries. The purpose of this review is to assess whether anthracycline chemotherapy exacerbates cardiotoxicity in patients with hypertension. A link between hypertension comorbidity and anthracycline-induced cardiotoxicity (AIC) was first suggested in 1979. Subsequent preclinical and clinical studies have supported the notion that hypertension is a major risk factor for AIC, along with the cumulative anthracycline dosage. There are several common or overlapping pathological mechanisms in AIC and hypertension, such as oxidative stress. Current evidence supports the utility of cardioprotective modalities as adjunct treatment prior to and during anthracycline chemotherapy. Several promising cardioprotective approaches against AIC pathologies include dexrazoxane, early hypertension management, and dietary supplementation of nitrate with beetroot juice or other medicinal botanical derivatives (e.g., visnagin and Danshen), which have both antihypertensive and anti-AIC properties. Future research is warranted to further elucidate the mechanisms of hypertension and AIC comorbidity and to conduct well-controlled clinical trials for identifying effective clinical strategies to improve long-term prognoses in this subgroup of cancer patients.
Topics: Animals; Antineoplastic Agents; Cardiotonic Agents; Cardiotoxicity; Dietary Supplements; Disease Progression; Humans; Hypertension
PubMed: 27829985
DOI: 10.1155/2016/8139861 -
Cardiovascular Drugs and Therapy Apr 2020Doxorubicin is a commonly used chemotherapeutic agent for the treatment of a range of cancers, but despite its success in improving cancer survival rates, doxorubicin is... (Review)
Review
Doxorubicin is a commonly used chemotherapeutic agent for the treatment of a range of cancers, but despite its success in improving cancer survival rates, doxorubicin is cardiotoxic and can lead to congestive heart failure. Therapeutic options for this patient group are limited to standard heart failure medications with the only drug specific for doxorubicin cardiotoxicity to reach FDA approval being dexrazoxane, an iron-chelating agent targeting oxidative stress. However, dexrazoxane has failed to live up to its expectations from preclinical studies while also bringing up concerns about its safety. Despite decades of research, the molecular mechanisms of doxorubicin cardiotoxicity are still poorly understood and oxidative stress is no longer considered to be the sole evil. Mitochondrial impairment, increased apoptosis, dysregulated autophagy and increased fibrosis have also been shown to be crucial players in doxorubicin cardiotoxicity. These cellular processes are all linked by one highly conserved intracellular kinase: adenosine monophosphate-activated protein kinase (AMPK). AMPK regulates mitochondrial biogenesis via PGC1α signalling, increases oxidative mitochondrial metabolism, decreases apoptosis through inhibition of mTOR signalling, increases autophagy through ULK1 and decreases fibrosis through inhibition of TGFβ signalling. AMPK therefore sits at the control point of many mechanisms shown to be involved in doxorubicin cardiotoxicity and cardiac AMPK signalling itself has been shown to be impaired by doxorubicin. In this review, we introduce different agents known to activate AMPK (metformin, statins, resveratrol, thiazolidinediones, AICAR, specific AMPK activators) as well as exercise and dietary restriction, and we discuss the existing evidence for their potential role in cardioprotection from doxorubicin cardiotoxicity.
Topics: AMP-Activated Protein Kinases; Aminoimidazole Carboxamide; Animals; Antibiotics, Antineoplastic; Caloric Restriction; Cardiotoxicity; Doxorubicin; Enzyme Activation; Enzyme Activators; Exercise; Heart Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Metformin; Mitochondria, Heart; Myocytes, Cardiac; Resveratrol; Ribonucleotides; Signal Transduction; Thiazolidinediones
PubMed: 32034646
DOI: 10.1007/s10557-020-06941-x -
JACC. CardioOncology Sep 2019
PubMed: 34396165
DOI: 10.1016/j.jaccao.2019.08.011 -
JACC. CardioOncology Nov 2022Trametinib is a MEK1 (mitogen-activated extracellular signal-related kinase kinase 1) inhibitor used in the treatment of BRAF (rapid accelerated fibrosarcoma...
BACKGROUND
Trametinib is a MEK1 (mitogen-activated extracellular signal-related kinase kinase 1) inhibitor used in the treatment of BRAF (rapid accelerated fibrosarcoma B-type)-mutated metastatic melanoma. Roughly 11% of patients develop cardiomyopathy following long-term trametinib exposure. Although described clinically, the molecular landscape of trametinib cardiotoxicity has not been characterized.
OBJECTIVES
The aim of this study was to test the hypothesis that trametinib promotes widespread transcriptomic and cellular changes consistent with oxidative stress and impairs cardiac function.
METHODS
Mice were treated with trametinib (1 mg/kg/d). Echocardiography was performed pre- and post-treatment. Gross, histopathologic, and biochemical assessments were performed to probe for molecular and cellular changes. Human cardiac organoids were used as an in vitro measurement of cardiotoxicity and recovery.
RESULTS
Long-term administration of trametinib was associated with significant reductions in survival and left ventricular ejection fraction. Histologic analyses of the heart revealed myocardial vacuolization and calcification in 28% of animals. Bulk RNA sequencing identified 435 differentially expressed genes and 116 differential signaling pathways following trametinib treatment. Upstream gene analysis predicted interleukin-6 as a regulator of 17 relevant differentially expressed genes, suggestive of PI3K/AKT and JAK/STAT activation, which was subsequently validated. Trametinib hearts displayed elevated markers of oxidative stress, myofibrillar degeneration, an 11-fold down-regulation of the apelin receptor, and connexin-43 mislocalization. To confirm the direct cardiotoxic effects of trametinib, human cardiac organoids were treated for 6 days, followed by a 6-day media-only recovery. Trametinib-treated organoids exhibited reductions in diameter and contractility, followed by partial recovery with removal of treatment.
CONCLUSIONS
These data describe pathologic changes observed in trametinib cardiotoxicity, supporting the exploration of drug holidays and alternative pharmacologic strategies for disease prevention.
PubMed: 36444237
DOI: 10.1016/j.jaccao.2022.07.009