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Frontiers in Molecular Biosciences 2022Triple-negative breast cancer (TNBC) is one of the most lethal subtypes of breast cancer (BC), and it accounts for approximately 10%-20% of all invasive BCs diagnosed...
Triple-negative breast cancer (TNBC) is one of the most lethal subtypes of breast cancer (BC), and it accounts for approximately 10%-20% of all invasive BCs diagnosed worldwide. The survival rate of TNBC in stages III and IV is very low, and a large number of patients are diagnosed in these stages. Therefore, the purpose of this study was to identify TNBC-causing molecular signatures and anti-TNBC drug agents for early diagnosis and therapies. Five microarray datasets that contained 304 TNBC and 109 control samples were collected from the Gene Expression Omnibus (GEO) database, and RNA-Seq data with 116 tumor and 124 normal samples were collected from TCGA database to identify differentially expressed genes (DEGs) between TNBC and control samples. A total of 64 DEGs were identified, of which 29 were upregulated and 35 were downregulated, by using the statistical limma R-package. Among them, seven key genes (KGs) were commonly selected from microarray and RNA-Seq data based on the high degree of connectivity through PPI (protein-protein interaction) and module analysis. Out of these seven KGs, six KGs (TOP2A, BIRC5, AURKB, ACTB, ASPM, and BUB1B) were upregulated and one (EGFR) was downregulated. We also investigated their differential expression patterns with different subtypes and progression stages of BC by the independent datasets of RNA-seq profiles from UALCAN database, which indicated that they may be potential biomarkers for early diagnosis. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses with the proposed DEGs were performed using the online Enrichr database to investigate the pathogenetic processes of TNBC highlighting KGs. Then, we performed gene regulatory network analysis and identified three transcriptional (SOX2, E2F4, and KDM5B) and three post-transcriptional (hsa-mir-1-3p, hsa-mir-124-3p, and hsa-mir-34a-5p) regulators of KGs. Finally, we proposed five KG-guided repurposable drug molecules (imatinib, regorafenib, pazopanib, teniposide, and dexrazoxane) for TNBC through network pharmacology and molecular docking analyses. These drug molecules also showed significant binding performance with some cancer-related PTM-sites (phosphorylation, succinylation, and ubiquitination) of top-ranked four key proteins (EGFR, AURKB, BIRC5, and TOP2A). Therefore, the findings of this computational study may play a vital role in early diagnosis and therapies against TNBC by wet-lab validation.
PubMed: 36567949
DOI: 10.3389/fmolb.2022.1049741 -
Journal of Indian Association of... 2022Extravasation of chemotherapeutic agents from a peripheral cannula is a known problem, and to prevent that, oncology units use central vein access with indwelling...
Extravasation of chemotherapeutic agents from a peripheral cannula is a known problem, and to prevent that, oncology units use central vein access with indwelling catheters such as port-a-cath or Hickman catheter. The intrapleural extravasation of chemotherapeutic agents is a rare event. We describe a 9-year-old girl with newly diagnosed Ewing's sarcoma of the left upper humerus receiving neoadjuvant chemotherapy through a newly inserted port-a-cath device. The patient developed tachypnea and right-sided chest pain on day 2 of chemotherapy. The radiological investigations confirmed the extravasation of doxorubicin into the pleural space. The surgical washout with chest-drain insertion was done, and we continued flushing with normal saline until the drain fluid became clear. She has completed neoadjuvant therapy. This case report shines light into scenarios where extravasation of anthracycline into the pleural cavity or thorax can be managed conservatively and in settings where dexrazoxane is unavailable without causing much delay in restarting the chemotherapy.
PubMed: 36530827
DOI: 10.4103/jiaps.jiaps_253_21 -
Nature Communications Dec 2022Distressing and lethal cardiotoxicity is one of the major severe side effects of using anthracycline drugs such as doxorubicin for cancer chemotherapy. The currently...
Distressing and lethal cardiotoxicity is one of the major severe side effects of using anthracycline drugs such as doxorubicin for cancer chemotherapy. The currently available strategy to counteract these side effects relies on the administration of cardioprotective agents such as Dexrazoxane, which unfortunately has unsatisfactory efficacy and produces secondary myelosuppression. In the present work, aiming to target the characteristic ferrous iron overload in the doxorubicin-contaminated cardiac microenvironment, a biocompatible nanomedicine prepared by the polyvinylpyrrolidone-directed assembly of magnesium hexacyanoferrate nanocatalysts is designed and constructed for highly efficient intracellular ferrous ion capture and antioxidation. The synthesized magnesium hexacyanoferrate nanocatalysts display prominent superoxide radical dismutation and catalytic HO decomposition activities to eliminate cytotoxic radical species. Excellent in vitro and in vivo cardioprotection from these magnesium hexacyanoferrate nanocatalysts are demonstrated, and the underlying intracellular ferrous ion traffic regulation mechanism has been explored in detail. The marked cardioprotective effect and biocompatibility render these magnesium hexacyanoferrate nanocatalysts to be highly promising and clinically transformable cardioprotective agents that can be employed during cancer treatment.
Topics: Humans; Cardiotoxicity; Magnesium; Cardiotonic Agents; Iron; Hydrogen Peroxide; Doxorubicin
PubMed: 36522337
DOI: 10.1038/s41467-022-35503-y -
Journal of Cancer Research and... Dec 2022Skin reactions after transarterial chemoembolization (TACE) with anthracyclines are rare and mostly limited to small areas. We describe a 56-year-old male with...
Dexrazoxane for rapid extended livedo reticularis-like skin reaction due to systemic epirubicin diffusion during transcatheter arterial chemoembolization procedure for hepatocellular carcinoma.
Skin reactions after transarterial chemoembolization (TACE) with anthracyclines are rare and mostly limited to small areas. We describe a 56-year-old male with hepatocellular carcinoma treated with epirubicin chemoembolization. Immediately the procedure, pain on the right side and an extended livedo reticularis-like skin reaction appeared. Since dexrazoxane, a topoisomerase-II catalytic-cycle inhibitor, has been shown to be effective in preventing or reducing skin necrosis and ulceration following anthracycline extravasation, the drug was administered 8 h after TACE and repeated in the following 2 days. Due to marked extrahepatic diffusion of epirubicin as evidenced by computed tomography imaging, the patient showed signs of systemic organ involvement. The critically ill patient required close follow-up and intensified treatment including blood supply and pulmonary drainage of a pleural effusion. The patient presented a significant clinical improvement of the skin lesions and resolution of organ involvement with normalization of laboratory parameters after dexrazoxane. In conclusion, adverse extended skin reactions and severe systemic effects related to anthracyclines diffusion could be properly treated with dexrazoxane infusion.
Topics: Male; Humans; Middle Aged; Carcinoma, Hepatocellular; Epirubicin; Chemoembolization, Therapeutic; Liver Neoplasms; Antibiotics, Antineoplastic; Anthracyclines; Topoisomerase II Inhibitors
PubMed: 36511016
DOI: 10.4103/jcrt.JCRT_574_20 -
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 -
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 -
Archives of Pharmacal Research Oct 2022Chemotherapy is a main treatment for cancer, and it benefits patients by controlling cancer relapse and metastasis, thereby leading to an increase in the overall... (Review)
Review
Chemotherapy is a main treatment for cancer, and it benefits patients by controlling cancer relapse and metastasis, thereby leading to an increase in the overall survival rate. However, this treatment is associated with mild to severe side effects, one of which is cardiotoxicity. The severity of cardiotoxicity, a leading cause of cardiovascular diseases, depends on the type of cancer therapy employed and the time required for its management. A chemotherapeutic agent is used either alone or in combination with other drugs for cancer treatment. The exact mechanism of chemotherapeutic agent-induced cardiotoxicity remains unclear, although it is likely to be multifactorial and to include oxidative stress, apoptosis, and inflammation. There are many approaches to avoid the untoward effects of chemotherapeutic agents. However, the available options for cardiac protection are minimal, and they include renin-angiotensin system blockers, beta-blockers, herbal drugs, or iron chelators such as dexrazoxane. The present review provides information on the molecular mechanism of chemotherapy-induced myocardial infarction and cardiotoxicity along with scientifically studied synthetic molecules, herbal extracts, and natural products to manage chemotherapy-induced cardiotoxicity.
Topics: Humans; Cardiotoxicity; Antineoplastic Agents; Heart; Neoplasms; Oxidative Stress; Cardiotonic Agents
PubMed: 36306018
DOI: 10.1007/s12272-022-01411-4 -
Biomedicine & Pharmacotherapy =... Dec 2022Doxorubicin (DOX), as a kind of chemotherapy agent with remarkable therapeutic effect, can be used to treat diverse malignant tumors clinically. Dose-dependent... (Review)
Review
Doxorubicin (DOX), as a kind of chemotherapy agent with remarkable therapeutic effect, can be used to treat diverse malignant tumors clinically. Dose-dependent cardiotoxicity is the most serious adverse reaction after DOX treatment, which eventually leads to cardiomyopathy and greatly limits the clinical application of DOX. DOX-induced cardiomyopathy is not a result of a single mechanistic action, and multiple mechanisms have been discovered and demonstrated experimentally, such as oxidative stress, inflammation, mitochondrial damage, calcium homeostasis disorder, ferroptosis, autophagy and apoptosis. Dexrazoxane (DEX) is the only protective agent approved by FDA for the treatment of DOX cardiomyopathy, but its clinical treatment still has some limitations. Therefore, we need to find other effective therapeutic drugs as soon as possible. In this paper, the drugs that effectively improve cardiomyopathy in recent years are mainly described from the aspects of natural drugs, endogenous substances, new dosage forms, herbal medicines, chemical modification and marketed drugs. The aim of the present study is to evaluate the effects of these drugs on DOX-induced anticancer and cardiomyopathy curative effects, so as to provide some reference value for clinical treatment of DOX-induced cardiomyopathy in the future.
Topics: Humans; Myocytes, Cardiac; Cardiotoxicity; Doxorubicin; Cardiomyopathies; Apoptosis; Oxidative Stress
PubMed: 36279722
DOI: 10.1016/j.biopha.2022.113903 -
The Lancet. Child & Adolescent Health Dec 2022Survivors of childhood cancer are at risk of anthracycline-induced cardiotoxicity, which might be prevented by dexrazoxane. However, concerns exist about the safety of... (Review)
Review
Primary cardioprotection with dexrazoxane in patients with childhood cancer who are expected to receive anthracyclines: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.
Survivors of childhood cancer are at risk of anthracycline-induced cardiotoxicity, which might be prevented by dexrazoxane. However, concerns exist about the safety of dexrazoxane, and little guidance is available on its use in children. To facilitate global consensus, a working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the existing literature and used evidence-based methodology to develop a guideline for dexrazoxane administration in children with cancer who are expected to receive anthracyclines. Recommendations were made in consideration of evidence supporting the balance of potential benefits and harms, and clinical judgement by the expert panel. Given the dose-dependent risk of anthracycline-induced cardiotoxicity, we concluded that the benefits of dexrazoxane probably outweigh the risk of subsequent neoplasms when the cumulative doxorubicin or equivalent dose is at least 250 mg/m (moderate recommendation). No recommendation could be formulated for cumulative doxorubicin or equivalent doses of lower than 250 mg/m, due to insufficient evidence to determine whether the risk of cardiotoxicity outweighs the possible risk of subsequent neoplasms. Further research is encouraged to determine the long-term efficacy and safety of dexrazoxane in children with cancer.
Topics: Humans; Child; Anthracyclines; Dexrazoxane; Neoplasms; Cardiotoxicity; Antineoplastic Agents; Doxorubicin; Polyketides
PubMed: 36174614
DOI: 10.1016/S2352-4642(22)00239-5 -
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