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Nature Communications Sep 2022Microsporidia are a diverse group of fungal-related obligate intracellular parasites that infect most animal phyla. Despite the emerging threat that microsporidia...
Microsporidia are a diverse group of fungal-related obligate intracellular parasites that infect most animal phyla. Despite the emerging threat that microsporidia represent to humans and agricultural animals, few reliable treatment options exist. Here, we develop a high-throughput screening method for the identification of chemical inhibitors of microsporidia infection, using liquid cultures of Caenorhabditis elegans infected with the microsporidia species Nematocida parisii. We screen a collection of 2560 FDA-approved compounds and natural products, and identify 11 candidate microsporidia inhibitors. Five compounds prevent microsporidia infection by inhibiting spore firing, whereas one compound, dexrazoxane, slows infection progression. The compounds have in vitro activity against several other microsporidia species, including those known to infect humans. Together, our results highlight the effectiveness of C. elegans as a model host for drug discovery against intracellular pathogens, and provide a scalable high-throughput system for the identification and characterization of microsporidia inhibitors.
Topics: Animals; Biological Products; Caenorhabditis elegans; Cell Proliferation; Dexrazoxane; Humans; Microsporidia; Microsporidiosis
PubMed: 36163337
DOI: 10.1038/s41467-022-33400-y -
The Cochrane Database of Systematic... Sep 2022This review is the third update of a previously published Cochrane Review. The original review, looking at all possible cardioprotective agents, was split and this part... (Review)
Review
BACKGROUND
This review is the third update of a previously published Cochrane Review. The original review, looking at all possible cardioprotective agents, was split and this part now focuses on dexrazoxane only. Anthracyclines are effective chemotherapeutic agents in the treatment of numerous malignancies. Unfortunately, their use is limited by a dose-dependent cardiotoxicity. In an effort to prevent or reduce this cardiotoxicity, different cardioprotective agents have been studied, including dexrazoxane.
OBJECTIVES
To assess the efficacy of dexrazoxane to prevent or reduce cardiotoxicity and determine possible effects of dexrazoxane on antitumour efficacy, quality of life and toxicities other than cardiac damage in adults and children with cancer receiving anthracyclines when compared to placebo or no additional treatment.
SEARCH METHODS
We searched CENTRAL, MEDLINE and Embase to May 2021. We also handsearched reference lists, the proceedings of relevant conferences and ongoing trials registers.
SELECTION CRITERIA
Randomised controlled trials (RCTs) in which dexrazoxane was compared to no additional therapy or placebo in adults and children with cancer receiving anthracyclines.
DATA COLLECTION AND ANALYSIS
Two review authors independently performed study selection, data extraction, risk of bias and GRADE assessment of included studies. We analysed results in adults and children separately. We performed analyses according to the Cochrane Handbook for Systematic Reviews of Interventions.
MAIN RESULTS
For this update, we identified 548 unique records. We included three additional RCTs: two paediatric and one adult. Therefore, we included a total of 13 eligible RCTs (five paediatric and eight adult). The studies enrolled 1252 children with leukaemia, lymphoma or a solid tumour and 1269 participants, who were mostly diagnosed with breast cancer. In adults, moderate-quality evidence showed that there was less clinical heart failure with the use of dexrazoxane (risk ratio (RR) 0.22, 95% confidence interval (CI) 0.11 to 0.43; 7 studies, 1221 adults). In children, we identified no difference in clinical heart failure risk between treatment groups (RR 0.20, 95% CI 0.01 to 4.19; 3 studies, 885 children; low-quality evidence). In three paediatric studies assessing cardiomyopathy/heart failure as the primary cause of death, none of the children had this outcome (1008 children, low-quality evidence). In the adult studies, different definitions for subclinical myocardial dysfunction and clinical heart failure combined were used, but pooled analyses were possible: there was a benefit in favour of the use of dexrazoxane (RR 0.37, 95% CI 0.24 to 0.56; 3 studies, 417 adults and RR 0.46, 95% CI 0.33 to 0.66; 2 studies, 534 adults, respectively, moderate-quality evidence). In the paediatric studies, definitions of subclinical myocardial dysfunction and clinical heart failure combined were incomparable, making pooling impossible. One paediatric study showed a benefit in favour of dexrazoxane (RR 0.33, 95% CI 0.13 to 0.85; 33 children; low-quality evidence), whereas another study showed no difference between treatment groups (Fischer exact P = 0.12; 537 children; very low-quality evidence). Overall survival (OS) was reported in adults and overall mortality in children. The meta-analyses of both outcomes showed no difference between treatment groups (hazard ratio (HR) 1.04, 95% 0.88 to 1.23; 4 studies; moderate-quality evidence; and HR 1.01, 95% CI 0.72 to 1.42; 3 studies, 1008 children; low-quality evidence, respectively). Progression-free survival (PFS) was only reported in adults. We subdivided PFS into three analyses based on the comparability of definitions, and identified a longer PFS in favour of dexrazoxane in one study (HR 0.62, 95% CI 0.43 to 0.90; 164 adults; low-quality evidence). There was no difference between treatment groups in the other two analyses (HR 0.95, 95% CI 0.64 to 1.40; 1 study; low-quality evidence; and HR 1.18, 95% CI 0.97 to 1.43; 2 studies; moderate-quality evidence, respectively). In adults, there was no difference in tumour response rate between treatment groups (RR 0.91, 95% CI 0.79 to 1.04; 6 studies, 956 adults; moderate-quality evidence). We subdivided tumour response rate in children into two analyses based on the comparability of definitions, and identified no difference between treatment groups (RR 1.01, 95% CI 0.95 to 1.07; 1 study, 206 children; very low-quality evidence; and RR 0.92, 95% CI 0.84 to 1.01; 1 study, 200 children; low-quality evidence, respectively). The occurrence of secondary malignant neoplasms (SMN) was only assessed in children. The available and worst-case analyses were identical and showed a difference in favour of the control group (RR 3.08, 95% CI 1.13 to 8.38; 3 studies, 1015 children; low-quality evidence). In the best-case analysis, the direction of effect was the same, but there was no difference between treatment groups (RR 2.51, 95% CI 0.96 to 6.53; 4 studies, 1220 children; low-quality evidence). For other adverse effects, results also varied. None of the studies evaluated quality of life. If not reported, the number of participants for an analysis was unclear.
AUTHORS' CONCLUSIONS
Our meta-analyses showed the efficacy of dexrazoxane in preventing or reducing cardiotoxicity in adults treated with anthracyclines. In children, there was a difference between treatment groups for one cardiac outcome (i.e. for one of the definitions used for clinical heart failure and subclinical myocardial dysfunction combined) in favour of dexrazoxane. In adults, no evidence of a negative effect on tumour response rate, OS and PFS was identified; and in children, no evidence of a negative effect on tumour response rate and overall mortality was identified. The results for adverse effects varied. In children, dexrazoxane may be associated with a higher risk of SMN; in adults this was not addressed. In adults, the quality of the evidence ranged between moderate and low; in children, it ranged between low and very low. Before definitive conclusions on the use of dexrazoxane can be made, especially in children, more high-quality research is needed. We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in children and adults with cancer who are treated with anthracyclines. However, clinicians and patients should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects, including SMN, for each individual. For children, the International Late Effects of Childhood Cancer Guideline Harmonization Group has developed a clinical practice guideline.
Topics: Adult; Anthracyclines; Antibiotics, Antineoplastic; Cardiotonic Agents; Cardiotoxicity; Child; Dexrazoxane; Heart Failure; Humans; Leukemia, Myeloid, Acute; Polyketides; Systematic Reviews as Topic
PubMed: 36162822
DOI: 10.1002/14651858.CD014638.pub2 -
Current Oncology (Toronto, Ont.) Sep 2022Childhood and adolescent cancer survivors are disproportionately more likely to develop cardiovascular diseases from the late effects of cardiotoxic therapies (e.g.,... (Review)
Review
Childhood and adolescent cancer survivors are disproportionately more likely to develop cardiovascular diseases from the late effects of cardiotoxic therapies (e.g., anthracycline-based chemotherapy and chest-directed radiotherapy). Currently, dexrazoxane is the only approved drug for preventing cancer treatment-related cardiac damage. While animal models highlight the beneficial effects of exercise cancer treatment-related cardiac dysfunction, few clinical studies have been conducted. Thus, the objective of this scoping review was to explore the designs and impact of exercise-based interventions for managing cancer treatment-related cardiac dysfunction in childhood and adolescent cancer survivors. Reviewers used Joanna Briggs Institute's methodology to identify relevant literature. Then, 4616 studies were screened, and three reviewers extracted relevant data from six reports. Reviewers found that exercise interventions to prevent cancer treatment-related cardiac dysfunction in childhood and adolescent cancer survivors vary regarding frequency, intensity, time, and type of exercise intervention. Further, the review suggests that exercise promotes positive effects on managing cancer treatment-related cardiac dysfunction across numerous indices of heart health. However, the few clinical studies employing exercise interventions for childhood and adolescent cancer survivors highlight the necessity for more research in this area.
Topics: Anthracyclines; Cancer Survivors; Cardiotoxicity; Dexrazoxane; Heart Diseases; Humans; Neoplasms; Survivors
PubMed: 36135069
DOI: 10.3390/curroncol29090500 -
JACC. Basic To Translational Science Aug 2022Ischemia-reperfusion (I/R) injury is a promising therapeutic target to improve clinical outcomes after acute myocardial infarction. Ferroptosis, triggered by iron...
Ischemia-reperfusion (I/R) injury is a promising therapeutic target to improve clinical outcomes after acute myocardial infarction. Ferroptosis, triggered by iron overload and excessive lipid peroxides, is reportedly involved in I/R injury. However, its significance and mechanistic basis remain unclear. Here, we show that glutathione peroxidase 4 (GPx4), a key endogenous suppressor of ferroptosis, determines the susceptibility to myocardial I/R injury. Importantly, ferroptosis is a major mode of cell death in I/R injury, distinct from mitochondrial permeability transition (MPT)-driven necrosis. This suggests that the use of therapeutics targeting both modes is an effective strategy to further reduce the infarct size and thereby ameliorate cardiac remodeling after I/R injury. Furthermore, we demonstrate that heme oxygenase 1 up-regulation in response to hypoxia and hypoxia/reoxygenation degrades heme and thereby induces iron overload and ferroptosis in the endoplasmic reticulum (ER) of cardiomyocytes. Collectively, ferroptosis triggered by GPx4 reduction and iron overload in the ER is distinct from MPT-driven necrosis in both in vivo phenotype and in vitro mechanism for I/R injury. The use of therapeutics targeting ferroptosis in conjunction with cyclosporine A can be a promising strategy for I/R injury.
PubMed: 36061338
DOI: 10.1016/j.jacbts.2022.03.012 -
Journal of Cardiovascular Development... Aug 2022Cardiotoxicity is a significant complication of chemotherapeutic agents in cancer patients. Cardiovascular incidents including LV dysfunction, heart failure (HF), severe... (Review)
Review
Cardiotoxicity is a significant complication of chemotherapeutic agents in cancer patients. Cardiovascular incidents including LV dysfunction, heart failure (HF), severe arrhythmias, arterial hypertension, and death are associated with high morbidity and mortality. Risk stratification of cancer patients prior to initiation of chemotherapy is crucial, especially in high-risk patients for cardiotoxicity. The early identification and management of potential risk factors for cardiovascular side effects seems to contribute to the prevention or minimization of cardiotoxicity. Screening of cancer patients includes biomarkers such as cTnI and natriuretic peptide and imaging measurements such as LV function, global longitudinal strain, and cardiac MRI. Cardioprotective strategies have been investigated over the last two decades. These strategies for either primary or secondary prevention include medical therapy such as ACE inhibitors, ARBs, b-blockers, aldosterone antagonists, statins and dexrazoxane, physical therapy, and reduction of chemotherapeutic dosages. However, data regarding dosages, duration of medical therapy, and potential interactions with chemotherapeutic agents are still limited. Collaboration among oncologists, cardiologists, and cardio-oncologists could establish management cardioprotective strategies and approved follow-up protocols in patients with cancer receiving chemotherapy.
PubMed: 36005423
DOI: 10.3390/jcdd9080259 -
Frontiers in Genetics 2022Pyroptosis is a programmed cell death process mediated by the gasdermin (GSDM) protein. However, limited research has been conducted to comprehensively analyze the...
Pyroptosis is a programmed cell death process mediated by the gasdermin (GSDM) protein. However, limited research has been conducted to comprehensively analyze the contribution of the GSDM family in a pan-cancer setting. We systematically evaluated the gene expression, genetic variations, and prognostic values of the GSDM family members. Furthermore, we investigated the association between the expression of GSDM genes and immune subtypes, the tumor microenvironment (TME), the stemness index, and cancer drug sensitivities by means of a pan-cancer analysis. GSDM genes were highly upregulated in most of the tested cancers. Low-level mutation frequencies within GSDM genes were common across the examined types of cancer, and their expression levels were associated with prognosis, clinical characteristics, TME features, and stemness scores in several cancer types, particularly those of the urinary system. Importantly, we found that the expressions of , , and were higher in kidney carcinomas, and specifically kidney renal clear cell carcinoma (KIRC); which adversely impacted the patient outcome. We showed that was potentially the most useful biomarker for KIRC. The drug sensitivity analysis demonstrated that the expressions of GSDM genes were correlated with the sensitivity of tumor cells to treatment with chemotherapy drugs nelarabine, fluphenazine, dexrazoxane, bortezomib, midostaurin, and vincristine. GSDM genes were associated with tumor behaviors and may participate in carcinogenesis. The results of this study may therefore provide new directions for further investigating the role of GSDM genes as therapeutic targets in a pan-cancer setting.
PubMed: 36003332
DOI: 10.3389/fgene.2022.926796 -
Pharmacological Research Sep 2022Iron participates in myriad processes necessary to sustain life. During the past decades, great efforts have been made to understand iron regulation and function in... (Review)
Review
Iron participates in myriad processes necessary to sustain life. During the past decades, great efforts have been made to understand iron regulation and function in health and disease. Indeed, iron is associated with both physiological (e.g., immune cell biology and function and hematopoiesis) and pathological (e.g., inflammatory and infectious diseases, ferroptosis and ferritinophagy) processes, yet few studies have addressed the potential functional link between iron, the aforementioned processes and extramedullary hematopoiesis, despite the obvious benefits that this could bring to clinical practice. Further investigation in this direction will shape the future development of individualized treatments for iron-linked diseases and chronic inflammatory disorders, including extramedullary hematopoiesis, metabolic syndrome, cardiovascular diseases and cancer.
Topics: Ferroptosis; Hematopoiesis, Extramedullary; Homeostasis; Humans; Iron; Iron Metabolism Disorders
PubMed: 35933006
DOI: 10.1016/j.phrs.2022.106386 -
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 -
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 -
Rare Tumors 2022Patient-reported outcomes (PROs), including health-related quality of life, are recommended to be routinely collected in clinical trials, but data are limited from...
BACKGROUND
Patient-reported outcomes (PROs), including health-related quality of life, are recommended to be routinely collected in clinical trials, but data are limited from trials of sarcoma patients. In this analysis, pooled PRO data are reported from patients with advanced or metastatic soft tissue sarcoma (STS) enrolled to the ANNOUNCE phase III trial of doxorubicin-based therapy.
METHODS
ANNOUNCE was a phase III trial that randomized 509 patients with STS to receive up to eight cycles of doxorubicin with olaratumab or placebo, followed by single-agent olaratumab or placebo. Dexrazoxane was allowed at any cycle of treatment. Participants completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30, which is scored 0-100), and Brief Pain Inventory Short Form Modified (mBPI-sf, scored from 0-10) at each treatment cycle. A descriptive analysis of the longitudinal data was conducted overall and by cumulative dose of doxorubicin received to inform the clinical care of patients with STS. Worsening on the QLQ-C30 was defined as a change of 10 points or more at any post-baseline assessment. Worsening on the mPBI-sf was defined as an increase of ≥2 points from baseline.
RESULTS
The majority of participants completed the baseline and at least one subsequent PRO assessment within the trial ( = 460, 90.4% EORTC QLQ-C30; = 454, 89.2%, mBPI-sf). Patients with STS enrolled to the ANNOUNCE trial had clinically meaningful problems with physical function and pain before initiating doxorubicin. Overall, those with fewer symptoms or better function at baseline received higher cumulative doxorubicin dose throughout the study. At baseline, mean QLQ-C30 fatigue was 29.9 with a median time to first worsening of 0.9 months, and mean nausea/vomiting was 6.5 with 1.4 months until worsening; mean physical function was 78.3 with median time to worsening of 2.1 months and mean health status was 66.8 with median time to first worsening of 1.6 months. Median time to worsening of pain was 7.9 months.
CONCLUSION
Patients with advanced or metastatic sarcoma reported a relatively rapid decline in PROs during doxorubicin-based treatment, with patients with poorer symptoms at baseline (specifically fatigue), subsequently receiving less doxorubicin therapy. The availability of detailed summary data from the patient perspective during doxorubicin-based treatment may inform future care of these patients and can provide a resource for the development of PRO endpoints in future trials.
PubMed: 35547106
DOI: 10.1177/20363613221100033