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3 Biotech Apr 2023Based on the well-documented studies, numerous tumors episodically regress permanently without treatment. Knowing the host tissue-initiated causative factors would offer...
UNLABELLED
Based on the well-documented studies, numerous tumors episodically regress permanently without treatment. Knowing the host tissue-initiated causative factors would offer considerable translational applicability, as a permanent regression process may be therapeutically replicated on patients. For this, we developed a systems biological formulation of the regression process with experimental verification and identified the relevant candidate biomolecules for therapeutic utility. We devised a cellular kinetics-based quantitative model of tumor extinction in terms of the temporal behavior of three main tumor-lysis entities: DNA blockade factor, cytotoxic T-lymphocyte and interleukin-2. As a case study, we analyzed the time-wise biopsy and microarrays of spontaneously regressing melanoma and fibrosarcoma tumors in mammalian/human hosts. We analyzed the differentially expressed genes (DEGs), signaling pathways, and bioinformatics framework of regression. Additionally, prospective biomolecules that could cause complete tumor regression were investigated. The tumor regression process follows a first-order cellular dynamics with a small negative bias, as verified by experimental fibrosarcoma regression; the bias is necessary to eliminate the residual tumor. We identified 176 upregulated and 116 downregulated DEGs, and enrichment analysis showed that the most significant were downregulated cell-division genes: TOP2A-KIF20A-KIF23-CDK1-CCNB1. Moreover, Topoisomerase-IIA inhibition might actuate spontaneous regression, with collateral confirmation provided from survival and genomic analysis of melanoma patients. Candidate molecules such as Dexrazoxane/Mitoxantrone, with interleukin-2 and antitumor lymphocytes, may potentially replicate permanent tumor regression process of melanoma. To conclude, episodic permanent tumor regression is a unique biological reversal process of malignant progression, and signaling pathway understanding, with candidate biomolecules, may plausibly therapeutically replicate the regression process on tumors clinically.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s13205-023-03515-0.
PubMed: 36890970
DOI: 10.1007/s13205-023-03515-0 -
Scientific Reports Feb 2023Despite high anticancer activity, doxorubicin (DOX)-induced cardiotoxicity (DIC) limits the extensive utility of DOX in a clinical setting. Amongst various strategies...
Despite high anticancer activity, doxorubicin (DOX)-induced cardiotoxicity (DIC) limits the extensive utility of DOX in a clinical setting. Amongst various strategies explored, dexrazoxane (DEX) remains the only cardioprotective agent to be approved for DIC. In addition, altering the dosing regimen of DOX has also proved to be somewhat beneficial in decreasing the risk of DIC. However, both approaches have limitations and further studies are required to better optimize them for maximal beneficial effects. In the present work, we quantitatively characterized DIC as well as the protective effects of DEX in an in vitro model of human cardiomyocytes, by means of experimental data and mathematical modeling and simulation (M&S) approaches. We developed a cellular-level, mathematical toxicodynamic (TD) model to capture the dynamic in vitro drug-drug interaction, and relevant parameters associated with DIC and DEX cardio-protection were estimated. Subsequently, we executed in vitro-in vivo translation by simulating clinical PK profiles for different dosing regimens of DOX alone and in combinations with DEX and using the simulated PK profiles to drive the cell-based TD models to evaluate the effects of long-term, clinical dosing regimens of these drugs on the relative cell viability of AC16 and to determine optimal drug combinations with minimal cellular toxicity. Here, we identified that the Q3W (once every three weeks) DOX regimen with 10:1 DEX:DOX dose ratio over three cycles (nine weeks) may offer maximal cardio-protection. Overall, the cell-based TD model can be effectively used to better design subsequent preclinical in vivo studies aimed for further optimizing safe and effective DOX and DEX combinations to mitigate DIC.
Topics: Humans; Dexrazoxane; Doxorubicin; Myocytes, Cardiac; Cardiotonic Agents; Cardiotoxicity
PubMed: 36813809
DOI: 10.1038/s41598-023-29964-4 -
Nutrients Jan 2023Iron functions as an essential micronutrient and participates in normal physiological and biochemical processes in the cardiovascular system. Ferroptosis is a novel type... (Review)
Review
Iron functions as an essential micronutrient and participates in normal physiological and biochemical processes in the cardiovascular system. Ferroptosis is a novel type of iron-dependent cell death driven by iron accumulation and lipid peroxidation, characterized by depletion of glutathione and suppression of glutathione peroxidase 4 (GPX4). Dysregulation of iron metabolism and ferroptosis have been implicated in the occurrence and development of cardiovascular diseases (CVDs), including hypertension, atherosclerosis, pulmonary hypertension, myocardial ischemia/reperfusion injury, cardiomyopathy, and heart failure. Iron chelators deferoxamine and dexrazoxane, and lipophilic antioxidants ferrostatin-1 and liproxstatin-1 have been revealed to abolish ferroptosis and suppress lipid peroxidation in atherosclerosis, cardiomyopathy, hypertension, and other CVDs. Notably, inhibition of ferroptosis by ferrostatin-1 has been demonstrated to alleviate cardiac impairments, fibrosis and pathological remodeling during hypertension by potentiating GPX4 signaling. Administration of deferoxamine improved myocardial ischemia/reperfusion injury by inhibiting lipid peroxidation. Several novel small molecules may be effective in the treatment of ferroptosis-mediated CVDs. In this article, we summarize the regulatory roles and underlying mechanisms of iron metabolism dysregulation and ferroptosis in the occurrence and development of CVDs. Targeting iron metabolism and ferroptosis are potential therapeutic strategies in the prevention and treatment of hypertension and other CVDs.
Topics: Humans; Ferroptosis; Cardiovascular Diseases; Myocardial Reperfusion Injury; Deferoxamine; Lipid Peroxidation; Iron; Hypertension
PubMed: 36771298
DOI: 10.3390/nu15030591 -
Journal of Clinical Oncology : Official... Apr 2023For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking.
PURPOSE
For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking.
METHODS
Within the Children's Oncology Group and the Dana Farber Cancer Institute's Childhood Acute Lymphoblastic Leukemia Consortium, we evaluated four randomized trials of children with acute lymphoblastic leukemia or Hodgkin lymphoma, who received doxorubicin with or without dexrazoxane, and a nonrandomized trial of patients with osteosarcoma who all received doxorubicin with dexrazoxane. Cumulative doxorubicin doses ranged from 100 to 600 mg/m across these five trials, and dexrazoxane was administered uniformly (10:1 mg/m ratio) as an intravenous bolus before doxorubicin. Cardiac function was prospectively assessed in survivors from these trials, plus a matched group of survivors of osteosarcoma treated with doxorubicin without dexrazoxane. Two-dimensional echocardiograms and blood biomarkers were analyzed centrally in blinded fashion. Multivariate analyses adjusted for demographic characteristics, cumulative doxorubicin dose, and chest radiotherapy determined the differences and associations by dexrazoxane status.
RESULTS
From 49 participating institutions, 195 participants were assessed at 18.1 ± 2.7 years since cancer diagnosis (51% dexrazoxane-exposed; cumulative doxorubicin dose 297 ± 91 mg/m). Dexrazoxane administration was associated with superior left ventricular fractional shortening (absolute difference, +1.4% [95% CI, 0.3 to 2.5]) and ejection fraction (absolute difference, +1.6% [95% CI, 0.0 to 3.2]), and lower myocardial stress per B-type natriuretic peptide (-6.7 pg/mL [95% CI, -10.6 to -2.8]). Dexrazoxane was associated with a reduced risk of having lower left ventricular function (fractional shortening < 30% or ejection fraction < 50%; odds ratio, 0.24 [95% CI, 0.07 to 0.81]). This protective association was primarily seen in those treated with cumulative doxorubicin doses ≥ 250 mg/m.
CONCLUSION
Among young adult-aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure.
Topics: Young Adult; Child; Humans; Aged; Dexrazoxane; Cancer Survivors; Doxorubicin; Antibiotics, Antineoplastic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Osteosarcoma; Bone Neoplasms
PubMed: 36669148
DOI: 10.1200/JCO.22.02423 -
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 -
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 -
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