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Abstract Background Cardiotoxicity is a concern for patients with sarcoma receiving anthracyclines. Dexrazoxane reduces this risk; however, the timing of administration varies in practice. This study evaluated the association between dexrazoxane timing and anthracycline cardiotoxicity risk. Patients and methods This retrospective, single-center cohort study included adults with sarcoma treated with anthracyclines from 2010 to 2020 with a baseline and ≥1 follow-up echocardiogram. “Early” dexrazoxane was defined as starting with the first anthracycline dose; “later” as starting with the second or subsequent doses. The primary endpoint was time to cardiotoxicity (decline in left ventricular ejection fraction [LVEF] ≥10%-<50% from baseline). Associations were evaluated using multivariable Cox proportional hazards models. Results Among 672 patients, the median doxorubicin-equivalent dose was 300 mg/m2 (interquartile range [IQR]: 200-444 mg/m2); dexrazoxane was administered early in 130 patients (19.3%) and later in 275 (40.9%). Over a median follow-up of 8.6 months (IQR: 3.9-23.1 months), 48 (7.1%) developed cardiotoxicity. Among patients who received a cumulative anthracycline dose >300 mg/m2, those receiving early dexrazoxane had an 85% reduction in cardiotoxicity risk (hazard ratio, 0.15; 95% CI, 0.02-0.99) compared to those who did not receive dexrazoxane, adjusting for age, diabetes, and baseline LVEF. Early dexrazoxane was not significantly associated with cardiotoxicity risk among patients who received a cumulative anthracycline dose ≤300 mg/m2. Conclusions Early dexrazoxane is significantly associated with lower cardiotoxicity risk in adults with sarcoma receiving anthracycline doses >300 mg/m2. These findings support the potential benefit of early dexrazoxane use in patients at elevated risk for anthracycline-induced cardiotoxicity; however, further validation is warranted.

Dexrazoxane can prevent anthracycline-associated cardiotoxicity. However, in 2011, its use in children was contraindicated by the EMA over concerns of increased risk of infection, myelosuppression and second primary malignancies, and because its efficacy in children had not then been established. We review here the evidence published since 2011, which confirms that dexrazoxane is an effective cardioprotectant in children and adolescents, is not associated with an increased risk of second primary malignancies or excess early or late mortality and does not impair chemotherapy efficacy. Based on this evidence, the contraindication for children and adolescents requiring high doses of anthracyclines and at risk for cardiotoxicity was removed from the European labeling for dexrazoxane.

Doxorubicin (DOX) has been widely used as a cytotoxic chemotherapeutic. However, DOX has a number of side effects, such as myelotoxicity or gonadotoxicity, the most dangerous of which is cardiotoxicity. Cardiotoxicity can manifest as cardiac arrhythmias, myocarditis, and pericarditis; life-threatening late cardiotoxicity can result in heart failure months or years after the completion of chemotherapy. The development of late cardiomyopathy is not yet fully understood. The most important question is how DOX reprograms the cardiomyocyte, after which DOX is excreted from the body, initially without symptoms. However, clinically overt cardiomyopathy develops over the following months and years. Since the 1980s, DOX-induced disorders in cardiomyocytes have been thought to be related to oxidative stress and dependent on the Fe/reactive oxygen species (ROS) mechanism. That line of evidence was supported by dexrazoxane (DEX) protection, the only Food and Drug Administration (FDA)-approved drug for preventing DOX-induced cardiomyopathy, which complexes iron. Thus, the hypothesis related to Fe/ROS provides a plausible explanation for the induction of the development of late cardiomyopathy via DOX. However, in subsequent studies, DEX was used to identify another important mechanism in DOX-induced cardiomyopathy that is related to topoisomerase 2β (Top2β). Does the Top2β hypothesis explain the mechanisms of the development of DOX-dependent late heart failure? Several of these mechanisms have been identified to date, proving the involvement of Top2β in the regulation of the redox balance, including oxidative stress. Thus, the development of late cardiomyopathy can be explained based on mechanisms related to Top2β. In this review, we highlight free radical theory, iron imbalance, calcium overload, and finally, a theory based on Top2β.

The usage of doxorubicin is hampered by its life-threatening cardiotoxicity in clinical practice. Dexrazoxane is the only cardioprotective medicine approved by the FDA for preventing doxorubicin-induced cardiac toxicity. Nevertheless, the mechanism of dexrazoxane is incompletely understood. The aim of our study is to investigate the possible molecular mechanism of dexrazoxane against doxorubicin-induced cardiotoxicity. We established a doxorubicin-induced mouse and cardiomyocyte injury model. Male C57BL/6J mice were randomly distributed into a control group (Con), a doxorubicin treatment group (DOX), a doxorubicin plus dexrazoxane treatment group (DOX+DEX), and a dexrazoxane treatment group (DEX). Echocardiography and histology analyses were performed to evaluate heart function and structure. DNA laddering, qRT-PCR, and Western blot were performed on DOX-treated cardiomyocytes with/without DEX treatment in vitro. Cardiomyocytes were then transfected with miR-17-5p mimics or inhibitors in order to analyze its downstream target. Our results demonstrated that dexrazoxane has a potent effect on preventing cardiac injury induced by doxorubicin in vivo and in vitro by reducing cardiomyocyte apoptosis. MicroRNA plays an important role in cardiovascular diseases. Our data revealed that dexrazoxane could upregulate the expression of miR-17-5p, which plays a cytoprotective role in response to hypoxia by regulating cell apoptosis. Furthermore, the miRNA and protein analysis revealed that miR-17-5p significantly attenuated phosphatase and tensin homolog (PTEN) expression in cardiomyocytes exposed to doxorubicin. Taken together, dexrazoxane might exert a cardioprotective effect against doxorubicin-induced cardiomyocyte apoptosis by regulating the expression of miR-17-5p/PTEN cascade.

The significant role of topoisomerases in the control of DNA chain topology has been confirmed in numerous research conducted worldwide. The prevalence of these enzymes, as well as the key importance of topoisomerase in the proper functioning of cells, have made them the target of many scientific studies conducted all over the world. This article is a comprehensive review of knowledge about topoisomerases and their inhibitors collected over the years. Studies on the structure-activity relationship and molecular docking are one of the key elements driving drug development. In addition to information on molecular targets, this article contains details on the structure-activity relationship of described classes of compounds. Moreover, the work also includes details about the structure of the compounds that drive the mode of action of topoisomerase inhibitors. Finally, selected topoisomerases inhibitors at the stage of clinical trials and their potential application in the chemotherapy of various cancers are described.

The therapeutic efficacy of anthracycline antibiotic, doxorubicin (DOX), is hampered due to cardiotoxicity. The objective of the study was to explore the counteraction of blueberry (BB) extract and Dexrazoxane (DEX) in Dox-induced cardiotoxicity in Wistar rats. Screening of BB extract as well as DEX for protection the myocardium from Dox-induced oxidative stress was performed on seven groups (8 rats each): Control (normal diet for 14 days and IP injection of normal saline (10 ml/kg) on the 11th day), DOX control (normal diet for 14 days with a single DOX injection of 18 mg/kg on the 11th day), BB extract control (80 mg/kg), DEX (180 mg/kg on the 11th day), BB + DOX (80 mg/kg BB extract for 14 days with DOX on the 11th day, 18 mg/kg), DEX + DOX (180 mg/kg DEX 30 min before 18 mg/kg DOX on the 11th day), and a combined group BB + DOX + DEX. A significant increase in serum biomarkers cTnT, NT-proBNP, MPO and cardiac MDA, TOP II, and a significant decrease in GSH and SOD contents were observed in the cardiotoxic (DOX control) group. All these parameters were reversed significantly in all treated groups in comparison to cardiotoxic groups. The cardiotoxic group showed significant upregulation of miR-140-5p expression and significant downregulation of Sirt2 and Nrf2 expression reversed in all treated groups except miR-140-5p which showed unsignificant difference. The best ameliorative effect was observed in the combined group. The histopathological assessment of myocardial damage provided supportive evidence for the biochemical results obtained. In conclusion, the BB extract (80.0 mg/kg) can attenuate the DOX-induced oxidative stress, and it has the potential to be developed as an adjunct against DOX-induced cardiotoxicity in cancer patients who undergo anthracycline chemotherapy.

Apart from cardiotoxicity, the chemotherapeutic agent doxorubicin (DOX) provokes acute and long-term vascular toxicity. Dexrazoxane (DEXRA) is an effective drug for treatment of DOX-induced cardiotoxicity, yet it remains currently unknown whether DEXRA prevents vascular toxicity associated with DOX. Accordingly, the present study aimed to evaluate the protective potential of DEXRA against DOX-related vascular toxicity in a previously-established in vivo and ex vivo model of vascular dysfunction induced by 16 hour (h) DOX exposure. Vascular function was evaluated in the thoracic aorta in organ baths, 16h after administration of DOX (4 mg/kg) or DOX with DEXRA (40 mg/kg) to male C57BL6/J mice. In parallel, vascular reactivity was evaluated after ex vivo incubation (16h) of murine aortic segments with DOX (1 μM) or DOX with DEXRA (10 μM). In both in vivo and ex vivo experiments, DOX impaired acetylcholine-stimulated endothelium-dependent vasodilation. In the ex vivo setting, DOX additionally attenuated phenylephrine-elicited vascular smooth muscle cell (VSMC) contraction. Importantly, DEXRA failed to prevent DOX-induced endothelial dysfunction and hypocontraction. Furthermore, RT-qPCR and Western blotting showed that DOX decreased the protein levels of topoisomerase-IIβ (TOP-IIβ), a key target of DEXRA, in the heart, but not in the aorta. Additionally, the effect of N-acetylcysteine (NAC, 10 μM), a reactive oxygen species (ROS) scavenger, was evaluated ex vivo . NAC did not prevent DOX-induced impairment of acetylcholine-stimulated vasodilation. In conclusion, our results show that DEXRA fails to prevent vascular toxicity resulting from 16h DOX treatment. This may relate to DOX provoking vascular toxicity in a ROS- and TOP-IIβ-independent way, at least in the evaluated acute setting. However, it is important to mention that these findings only apply to the acute (16h) treatment period, and further research is warranted to delineate the therapeutic potential of DEXRA against vascular toxicity associated with longer-term repetitive DOX dosing.

Acute kidney injury (AKI) is a heterogeneous clinical complication with no existing definite or particular therapies. Therefore, molecular mechanisms and approaches for treating acute kidney injury are in urgent need. Herein, we demonstrated that dexrazoxane (DXZ), a U.S. Food and Drug Administration (FDA)-approved cardioprotective drug, can both functionally and histologically attenuate cisplatin or ischemia-reperfusion injury-induced AKI in vitro and in vivo via inhibiting ferroptosis specifically. This effect is characterized by decreasing lipid peroxidation, shown by the biomarker of oxidative stress 4-hydroxynonenal (HNE) and prostaglandinendoperoxide synthase 2 (Ptgs2), while reversing the downregulation of glutathione peroxidase 4 (GPX4) and ferritin 1 (FTH-1). Mechanistically, the results revealed that DXZ targeted at the renal tubule significantly inhibits ferroptosis by suppressing α -amino- β -carboxymuconate- ε -semialdehyde decarboxylase (ACMSD). Furthermore, the conjugation of dexrazoxane and polysialic acid (DXZ-PSA) is specifically designed and utilized to enhance the therapeutic effect of DXZ by long-term effect in the kidney, especially retention and targeting in the renal tubules. This study provides a novel therapeutic approach and mechanistic insight for AKI by inhibiting ferroptosis through a new type drug DXZ-PSA with the enhanced renal distribution.

The chemotherapeutic agent doxorubicin (DOX) leads to the loss of skeletal muscle and adipose tissue mass, contributing to cancer cachexia. Experimental research on the molecular mechanisms of long-term DOX treatment is modest, and its effect on both skeletal muscle and adipose tissue has not been studied in an integrative manner. Dexrazoxane (DEXRA) is used to prevent DOX-induced cancer-therapy-related cardiovascular dysfunction (CTRCD), but its impact on skeletal muscle and adipose tissue remains elusive. Therefore, this study aimed to investigate the long-term effects of DOX on adipose tissue and skeletal muscle metabolism, and evaluate whether DEXRA can mitigate these effects. To this end, 10-week-old male C57BL6/J mice (n = 32) were divided into four groups: (1) DOX, (2) DOX-DEXRA combined, (3) DEXRA and (4) control. DOX (4 mg/kg weekly) and DEXRA (40 mg/kg weekly) were administered intraperitoneally over 6 weeks. Indirect calorimetry was used to assess metabolic parameters, followed by a molecular analysis and histological evaluation of skeletal muscle and adipose tissue. DOX treatment led to significant white adipose tissue (WAT) loss (74%) and moderate skeletal muscle loss (Gastrocnemius (GAS): 10%), along with decreased basal activity (53%) and energy expenditure (27%). A trend toward a reduced type IIa fiber cross-sectional area and a fast-to-slow fiber type switch in the Soleus muscle was observed. The WAT of DOX-treated mice displayed reduced Pparg (p < 0.0001), Cd36 (p < 0.0001) and Glut4 (p < 0.05) mRNA expression—markers of fat and glucose metabolism—compared to controls. In contrast, the GAS of DOX-treated mice showed increased Cd36 (p < 0.05) and Glut4 (p < 0.01), together with elevated Pdk4 (p < 0.001) mRNA expression—suggesting reduced carbohydrate oxidation—compared to controls. Additionally, DOX increased Murf1 (p < 0.05) and Atrogin1 (p < 0.05) mRNA expression—markers of protein degradation—compared to controls. In both the WAT and GAS of DOX-treated mice, Ppard mRNA expression remained unchanged. Overall, DEXRA failed to prevent these DOX-induced changes. Collectively, our results suggest that DOX induced varying degrees of wasting in adipose tissue and skeletal muscle, driven by distinct mechanisms. While DEXRA protected against DOX-induced CTRCD, it did not counteract its adverse effects on skeletal muscle and adipose tissue.

Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS production and possibly cellular iron accumulation. Here, we found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment. In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels. Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS and protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function. These results suggest that the cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against doxorubicin-induced cardiomyopathy.