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Scientific Reports Apr 2024Syndecan-binding protein (SDCBP) was reported to stimulate the advancement of esophageal squamous cell carcinoma (ESCC) and could potentially be a target for ESCC...
Syndecan-binding protein (SDCBP) was reported to stimulate the advancement of esophageal squamous cell carcinoma (ESCC) and could potentially be a target for ESCC treatment. There is a growing corpus of research on the anti-tumor effects of iron chelators; however, very few studies have addressed the involvement of dexrazoxane in cancer. In this study, structure-based virtual screening was employed to select drugs targeting SDCBP from the Food and Drug Administration (FDA)-approved drug databases. The sepharose 4B beads pull-down assay revealed that dexrazoxane targeted SDCBP by interacting with its PDZ1 domain. Additionally, dexrazoxane inhibited ESCC cell proliferation and anchorage-independent colony formation via SDCBP. ESCC cell apoptosis and G2 phase arrest were induced as measured by the flow cytometry assay. Subsequent research revealed that dexrazoxane attenuated the binding ability between SDCBP and EGFR in an immunoprecipitation assay. Furthermore, dexrazoxane impaired EGFR membrane localization and inactivated the EGFR/PI3K/Akt pathway. In vivo, xenograft mouse experiments indicated that dexrazoxane suppressed ESCC tumor growth. These data indicate that dexrazoxane might be established as a potential anti-cancer agent in ESCC by targeting SDCBP.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Proto-Oncogene Proteins c-akt; ErbB Receptors; Animals; Esophageal Neoplasms; Cell Proliferation; Mice; Phosphatidylinositol 3-Kinases; Signal Transduction; Syntenins; Cell Line, Tumor; Xenograft Model Antitumor Assays; Apoptosis; Mice, Nude; Antineoplastic Agents
PubMed: 38649770
DOI: 10.1038/s41598-024-59665-5 -
International Journal of Molecular... Feb 2024Late cardiotoxicity is a formidable challenge in anthracycline-based anticancer treatments. Previous research hypothesized that co-administration of carvedilol (CVD) and...
Assessment of the Impact of Carvedilol Administered Together with Dexrazoxan and Doxorubicin on Liver Structure and Function, Iron Metabolism, and Myocardial Redox System in Rats.
Late cardiotoxicity is a formidable challenge in anthracycline-based anticancer treatments. Previous research hypothesized that co-administration of carvedilol (CVD) and dexrazoxane (DEX) might provide superior protection against doxorubicin (DOX)-induced cardiotoxicity compared to DEX alone. However, the anticipated benefits were not substantiated by the findings. This study focuses on investigating the impact of CVD on myocardial redox system parameters in rats treated with DOX + DEX, examining its influence on overall toxicity and iron metabolism. Additionally, considering the previously observed DOX-induced ascites, a seldom-discussed condition, the study explores the potential involvement of the liver in ascites development. Compounds were administered weekly for ten weeks, with a specific emphasis on comparing parameter changes between DOX + DEX + CVD and DOX + DEX groups. Evaluation included alterations in body weight, feed and water consumption, and analysis of NADPH, NADP, NADPH/NADP, lipid peroxidation, oxidized DNA, and mRNA for superoxide dismutase 2 and catalase expressions in cardiac muscle. The iron management panel included markers for iron, transferrin, and ferritin. Liver abnormalities were assessed through histological examinations, aspartate transaminase, alanine transaminase, and serum albumin level measurements. During weeks 11 and 21, reduced NADPH levels were observed in almost all examined groups. Co-administration of DEX and CVD negatively affected transferrin levels in DOX-treated rats but did not influence body weight changes. Ascites predominantly resulted from cardiac muscle dysfunction rather than liver-related effects. The study's findings, exploring the impact of DEX and CVD on DOX-induced cardiotoxicity, indicate a lack of scientific justification for advocating the combined use of these drugs at histological, biochemical, and molecular levels.
Topics: Rats; Animals; Carvedilol; NADP; Cardiotoxicity; Ascites; Doxorubicin; Myocardium; Antibiotics, Antineoplastic; Iron; Lipid Peroxidation; Liver; Transferrin; Body Weight
PubMed: 38396896
DOI: 10.3390/ijms25042219 -
Current Treatment Options in Oncology Apr 2024Cardiotoxicity has emerged as a serious outcome catalyzed by various therapeutic targets in the field of cancer treatment, which includes chemotherapy, radiation, and... (Review)
Review
Cardiotoxicity has emerged as a serious outcome catalyzed by various therapeutic targets in the field of cancer treatment, which includes chemotherapy, radiation, and targeted therapies. The growing significance of cancer drug-induced cardiotoxicity (CDIC) and radiation-induced cardiotoxicity (CRIC) necessitates immediate attention. This article intricately unveils how cancer treatments cause cardiotoxicity, which is exacerbated by patient-specific risks. In particular, drugs like anthracyclines, alkylating agents, and tyrosine kinase inhibitors pose a risk, along with factors such as hypertension and diabetes. Mechanistic insights into oxidative stress and topoisomerase-II-B inhibition are crucial, while cardiac biomarkers show early damage. Timely intervention and prompt treatment, especially with specific agents like dexrazoxane and beta-blockers, are pivotal in the proactive management of CDIC.
Topics: Humans; Cardiotoxicity; Antineoplastic Agents; Neoplasms; Anthracyclines; Hematologic Neoplasms
PubMed: 38372853
DOI: 10.1007/s11864-023-01175-z -
Toxicological Sciences : An Official... Mar 2024Anthracyclines, such as doxorubicin (adriamycin), daunorubicin, or epirubicin, rank among the most effective agents in classical anticancer chemotherapy. However,...
Anthracyclines, such as doxorubicin (adriamycin), daunorubicin, or epirubicin, rank among the most effective agents in classical anticancer chemotherapy. However, cardiotoxicity remains the main limitation of their clinical use. Topoisomerase IIβ has recently been identified as a plausible target of anthracyclines in cardiomyocytes. We examined the putative topoisomerase IIβ selective agent XK469 as a potential cardioprotective and designed several new analogs. In our experiments, XK469 inhibited both topoisomerase isoforms (α and β) and did not induce topoisomerase II covalent complexes in isolated cardiomyocytes and HL-60, but induced proteasomal degradation of topoisomerase II in these cell types. The cardioprotective potential of XK469 was studied on rat neonatal cardiomyocytes, where dexrazoxane (ICRF-187), the only clinically approved cardioprotective, was effective. Initially, XK469 prevented daunorubicin-induced toxicity and p53 phosphorylation in cardiomyocytes. However, it only partially prevented the phosphorylation of H2AX and did not affect DNA damage measured by Comet Assay. It also did not compromise the daunorubicin antiproliferative effect in HL-60 leukemic cells. When administered to rabbits to evaluate its cardioprotective potential in vivo, XK469 failed to prevent the daunorubicin-induced cardiac toxicity in either acute or chronic settings. In the following in vitro analysis, we found that prolonged and continuous exposure of rat neonatal cardiomyocytes to XK469 led to significant toxicity. In conclusion, this study provides important evidence on the effects of XK469 and its combination with daunorubicin in clinically relevant doses in cardiomyocytes. Despite its promising characteristics, long-term treatments and in vivo experiments have not confirmed its cardioprotective potential.
Topics: Rats; Animals; Rabbits; Topoisomerase II Inhibitors; Anthracyclines; Cardiotoxicity; Daunorubicin; Doxorubicin; Antibiotics, Antineoplastic; DNA Topoisomerases, Type II; DNA Damage; Quinoxalines
PubMed: 38290791
DOI: 10.1093/toxsci/kfae008 -
JAMA Network Open Jan 2024Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but... (Clinical Trial)
Clinical Trial
IMPORTANCE
Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but also increased the cumulative doxorubicin dose, making overall treatment consequences for late cardiac toxic effects uncertain.
OBJECTIVE
To estimate the risk of cardiac toxic effects associated with treatments used in modern pediatric HL clinical trials.
DESIGN, SETTING, AND PARTICIPANTS
For this cohort study, Fine and Gray models were fitted using survivors in the Childhood Cancer Survivor Study who were diagnosed with HL between January 1, 1970, and December 31, 1999, and were followed for a median of 23.5 (range, 5.0-46.3) years. These models were applied to the exposures in the study population to estimate the 30-year cumulative incidence of cardiac disease. The study population comprised patients with intermediate-risk or high-risk HL treated in 4 consecutive Children's Oncology Group clinical trials from September 2002 to October 2022: AHOD0031, AHOD0831, AHOD1331, and S1826. Data analysis was performed from April 2020 to February 2023.
EXPOSURES
All patients received chemotherapy including doxorubicin, and some patients received mediastinal RT, dexrazoxane, or mediastinal RT and dexrazoxane.
MAIN OUTCOMES AND MEASURES
Estimated 30-year cumulative incidence of grade 3 to 5 cardiac disease.
RESULTS
The study cohort comprised 2563 patients, with a median age at diagnosis of 15 (range, 1-22) years. More than half of the patients were male (1357 [52.9%]). All 2563 patients received doxorubicin, 1362 patients (53.1%) received mediastinal RT, and 307 patients (12.0%) received dexrazoxane. Radiation therapy use and the median mean heart dose among patients receiving RT decreased, whereas the planned cumulative dose of doxorubicin and use of dexrazoxane cardioprotection increased. For patients treated at age 15 years, the estimated 30-year cumulative incidence of severe or fatal cardiac disease was 9.6% (95% CI, 4.2%-16.4%) in the AHOD0031 standard treatment group (enrolled 2002-2009), 8.6% (95% CI, 3.8%-14.9%) in the AHOD0831 trial (enrolled 2009-2012), 8.2% (95% CI, 3.6%-14.3%) in the AHOD1331 trial (enrolled 2015-2019), and 6.2% (95% CI, 2.7%-10.9%) in the S1826 trial (enrolled 2019-2022), whereas the expected rate in an untreated population was 5.0% (95% CI, 2.1%-9.3%). Despite the estimated reduction in late cardiac morbidity, the frequency of recommended echocardiographic screening among survivors will increase based on current guidelines.
CONCLUSIONS AND RELEVANCE
In this cohort study of sequential HL trials, reductions in the proportion of children receiving mediastinal RT and increases in dexrazoxane use were estimated to offset the increased doxorubicin dose and produce a net reduction in late cardiac disease. Further studies on dexrazoxane are warranted to confirm whether its role in reducing cardiac toxic effects is maintained long term. These findings suggest that survivorship follow-up guidelines should be refined to align with the risks associated with treatment.
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Infant; Male; Young Adult; Cardiotoxicity; Clinical Protocols; Cohort Studies; Dexrazoxane; Doxorubicin; Heart Diseases; Hodgkin Disease
PubMed: 38241048
DOI: 10.1001/jamanetworkopen.2023.51062 -
Advances in Pharmacological and... 2024The emergence of drug-resistant parasites impedes disease management and eradication efforts. Hence, a reinvigorated attempt to search for potent lead compounds in the...
BACKGROUND
The emergence of drug-resistant parasites impedes disease management and eradication efforts. Hence, a reinvigorated attempt to search for potent lead compounds in the mangroves is imperative.
AIM
This study evaluates antiplasmodial activity, antioxidant properties, and cytotoxicity of leaf alkaloidal extracts.
METHODS
The leaves were macerated with 70% ethanol to obtain a total crude extract. Dichloromethane and chloroform-isopropanol (3 : 1, v/v) were used to extract the crude alkaloids and quaternary alkaloids from the total crude. The antiplasmodial activities of the alkaloidal extracts were performed against 3D7 chloroquine-sensitive clone via the SYBR Green I fluorescence assay with artesunate serving as the reference drug. The alkaloidal extracts were further evaluated for antioxidant properties via the total antioxidant capacity (TAC), the total glutathione concentration (GSH), the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay, and the ferric-reducing antioxidant power (FRAP) methods. The cytotoxic activity of the alkaloidal extracts was tested on erythrocytes using a 3-(4,5-dimethylthiazol-2-yl)-5-diphenyltetrazolium bromide-MTT assay with little modification. The phytocompounds in the alkaloidal extracts were identified via gas chromatography-mass spectrometry (GC-MS) techniques.
RESULTS
The total crude extract showed good antiplasmodial activity (IC = 11.890 g/mL). The crude and quaternary alkaloidal extracts demonstrated promising antiplasmodial effects with IC values of 6.217 and 6.285 g/mL, respectively. The total crude and alkaloidal extracts showed good antioxidant properties with negligible cytotoxicity on erythrocytes with good selectivity indices. The GC-MS spectral analysis of crude alkaloidal extracts gave indole and isoquinoline alkaloids and several other compounds. Dexrazoxane was found to be the main compound predicted, with an 86% peak area in the quaternary alkaloidal extract.
CONCLUSION
The crude and quaternary alkaloidal extracts exhibited antiplasmodial activities and ability to inhibit oxidative stress with negligible toxicity on erythrocytes. This may be good characteristics to avoid oxidative stress related to infection in the treatment of malaria.
PubMed: 38235482
DOI: 10.1155/2024/4541581 -
Redox Biology Apr 2024Due to the cardiotoxicity of doxorubicin (DOX), its clinical application is limited. Lipid peroxidation caused by excessive ferrous iron is believed to be a key...
Due to the cardiotoxicity of doxorubicin (DOX), its clinical application is limited. Lipid peroxidation caused by excessive ferrous iron is believed to be a key molecular mechanism of DOX-induced cardiomyopathy (DIC). Dexrazoxane (DXZ), an iron chelator, is the only drug approved by the FDA for reducing DIC, but it has many side effects and cannot be used as a preventive drug in clinical practice. Single-nucleus RNA sequencing (snRNA-seq) analysis identified myocardial and epithelial cells that are susceptible to DOX-induced ferroptosis. The glutathione peroxidase 4 (GPX4) activator selenomethione (SeMet) significantly reduced polyunsaturated fatty acids (PUFAs) and oxidized lipid levels in vitro. Consistently, SeMet significantly decreased DOX-induced lipid peroxidation in H9C2 cells and mortality in C57BL/6 mice compared to DXZ, ferrostatin-1, and normal saline. SeMet can effectively reduce serum markers of cardiac injury in C57BL/6 mice and breast cancer patients. Depletion of the GPX4 gene in C57BL/6 mice resulted in an increase in polyunsaturated fatty acid (PUFA) levels and eliminated the protective effect of SeMet against DIC. Notably, SeMet exerted antitumor effects on breast cancer models with DOX while providing cardiac protection for the same animal without detectable toxicities. These findings suggest that pharmacological activation of GPX4 is a valuable and promising strategy for preventing the cardiotoxicity of doxorubicin.
Topics: Humans; Mice; Animals; Female; Phospholipid Hydroperoxide Glutathione Peroxidase; Cardiotoxicity; Mice, Inbred C57BL; Cardiomyopathies; Doxorubicin; Fatty Acids, Unsaturated; Breast Neoplasms
PubMed: 38232458
DOI: 10.1016/j.redox.2023.103024 -
PloS One 2023[This corrects the article DOI: 10.1371/journal.pone.0294848.].
[This corrects the article DOI: 10.1371/journal.pone.0294848.].
PubMed: 38117773
DOI: 10.1371/journal.pone.0296372 -
Frontiers in Cardiovascular Medicine 2023Pediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline...
BACKGROUND
Pediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline exposure. Early left ventricular systolic dysfunction (LVSD) compromises anthracycline delivery and is associated with inferior event-free and overall survival in pediatric AML. Thus, effective cardioprotective strategies and cardiotoxicity risk predictors are critical to optimize cancer therapy delivery and enable early interventions to prevent progressive LVSD. While dexrazoxane-based cardioprotection reduces short-term cardiotoxicity without compromising cancer survival, liposomal anthracycline formulations have the potential to mitigate cardiotoxicity while improving antitumor efficacy. This overview summarizes the rationale and methodology of cardiac substudies within AAML1831, a randomized Children's Oncology Group Phase 3 study of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in comparison with standard daunorubicin/cytarabine with dexrazoxane in the treatment of pediatric AML.
METHODS/DESIGN
Children (age <22 years) with newly diagnosed AML were enrolled and randomized to CPX-351-containing induction 1 and 2 (Arm A) or standard daunorubicin and dexrazoxane-containing induction (Arm B). Embedded cardiac correlative studies aim to compare the efficacy of this liposomal anthracycline formulation to dexrazoxane for primary prevention of cardiotoxicity by detailed core lab analysis of standardized echocardiograms and serial cardiac biomarkers throughout AML therapy and in follow-up. In addition, AAML1831 will assess the ability of early changes in sensitive echo indices (e.g., global longitudinal strain) and cardiac biomarkers (e.g., troponin and natriuretic peptides) to predict subsequent LVSD. Finally, AAML1831 establishes expert consensus-based strategies in cardiac monitoring and anthracycline dose modification to balance the potentially competing priorities of cardiotoxicity reduction with optimal leukemia therapy.
DISCUSSION
This study will inform diagnostic, prognostic, preventative, and treatment strategies regarding cardiotoxicity during pediatric AML therapy. Together, these measures have the potential to improve leukemia-free and overall survival and long-term cardiovascular health in children with AML. https://clinicaltrials.gov/, identifier NCT04293562.
PubMed: 38107263
DOI: 10.3389/fcvm.2023.1286241 -
Cancer Medicine Dec 2023To assess the occurrence of cardiotoxicity in patients with tumors receiving anthracycline-based chemotherapy, especially for sarcomas.
Evaluation of cardiotoxicity of anthracycline-containing chemotherapy regimens in patients with bone and soft tissue sarcomas: A study of the FDA adverse event reporting system joint single-center real-world experience.
OBJECTIVES
To assess the occurrence of cardiotoxicity in patients with tumors receiving anthracycline-based chemotherapy, especially for sarcomas.
METHODS
This study summarized the types and frequency of adverse events (AEs) for three anthracyclines from the FDA adverse event reporting system (FAERS) database. FAERS data from January 2004 to June 2022 were collected and analyzed. Disproportionality analyses, logistic regression, and descriptive analysis were used to compare the differences in cardiac disorders. A retrospective cohort study was conducted in a single center between December 2008 and May 2022. Our hospital-treated patients with bone and soft tissue sarcomas (BSTSs) with anthracycline-containing chemotherapy were analyzed. Serum markers, echocardiography, and electrocardiography have been used to evaluate cardiotoxic events.
RESULTS
One hundred thousand and seventy-five AE reports were obtained for doxorubicin (ADM), epirubicin (EPI), and liposome doxorubicin (L-ADM) from the FAERS database. ADM (OR = 3.1, p < 0.001), EPI (OR = 1.5, p < 0.001), and sarcomas (OR = 1.8, p < 0.001) may increase the probability of cardiac disorders. Cardiac failure, cardiotoxicity, and cardiomyopathy were anthracyclines' top 3 frequent AEs. Among patients receiving ADM-containing therapy, those with ADM applied at doses ≥75 mg/m /cycle were more likely to develop cardiac disorders than the other subgroups (OR = 3.5, p < 0.001). Patients younger than 18 are more likely to benefit from dexrazoxane prevention of cardiac failure. Six hundred and eighty-three patients with BSTSs receiving anthracycline-based chemotherapy were analyzed in our center. Patients receiving ADM-containing chemotherapy were likelier to experience abnormalities in serum troponin-T and left ventricular ejection fraction (p < 0.05). 2.0% (6/300) of patients receiving ADM-containing chemotherapy required adjustment of the chemotherapy regimen because of cardiotoxicity, whereas none were in the EPI or L-ADM groups.
CONCLUSIONS AND RELEVANCE
Among patients receiving anthracycline-containing therapy, patients with BSTSs were more likely to develop cardiac disorders than other tumors. In addition, patients with BSTSs receiving ADM chemotherapy had a higher likelihood of cardiotoxic events than those receiving EPI or L-ADM.
Topics: Humans; Anthracyclines; Cardiotoxicity; Retrospective Studies; Stroke Volume; Ventricular Function, Left; Antibiotics, Antineoplastic; Heart Diseases; Heart Failure; Doxorubicin; Epirubicin; Sarcoma; Soft Tissue Neoplasms
PubMed: 38054208
DOI: 10.1002/cam4.6730