ArticlePloS one2015
Mechanisms of Fatal Cardiotoxicity following High-Dose Cyclophosphamide Therapy and a Method for Its Prevention.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 57 citations in OpenAlex.
- Efficacy and safety of Busulfan-Fludarabine versus Busulfan-Cyclophosphamide as a conditioning regimen prior to hematopoietic stem cell transplant in hematologic malignancy patients: a meta-analysis of randomized controlled trials and observational studies.Therapeutic advances in hematology · 2026Article
- Determining Risk Factors Associated with Cardiovascular Complications in Patients with Acute Leukemia: A Systematic Review.Cancers · 2025Review
- Characterization of Pharmaceutical Transformation Products by High-Field Asymmetric Waveform Ion Mobility and Infrared Ion Spectroscopy Coupled to Mass Spectrometry.Journal of the American Society for Mass Spectrometry · 2025Article
- Early cardiac events after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide. subanalysis exploring cardiac toxicity conducted on behalf of GETH-TC.Frontiers in immunology · 2025Article
- Cardiac events occurring after allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide. Study conducted on behalf of the GETH-TC.Bone marrow transplantation · 2024Article
- Cardiac events after allo-HCT in patients with acute myeloid leukemia.Blood advances · 2024Article
- Cardiovascular Disease After Hematopoietic Stem Cell Transplantation in Adults:JACC. CardioOncology · 2024Review
- Low dose post-transplant cyclophosphamide and sirolimus induce mixed chimerism with CTLA4-Ig or lymphocyte depletion in an MHC-mismatched murine allotransplantation model.Bone marrow transplantation · 2024Article
- Effects of High-Dose Cyclophosphamide on Ultrastructural Changes and Gene Expression Profiles in the Cardiomyocytes ofDiseases (Basel, Switzerland) · 2024Article
- Review
- Early Impact of Mobilization Process on Cardiac Function and Size in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation.Journal of clinical medicine · 2024Article
- Article
- Lansoprazole attenuates cyclophosphamide-induced cardiopulmonary injury by modulating redox-sensitive pathways and inflammation.Molecular and cellular biochemistry · 2023Article
- Article
- Clinical features and outcomes of patients admitted to the ICU for Cyclophosphamide-associated cardiac toxicity: a retrospective cohort.Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer · 2023Article
- Incidence, risk factors, and impact of early cardiac toxicity after allogeneic hematopoietic cell transplant.Blood advances · 2023Article
- Biochemical, Histological, and Ultrastructural Studies of the Protective Role of Vitamin E on Cyclophosphamide-Induced Cardiotoxicity in Male Rats.Biomedicines · 2023Article
- MiRZhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2023Article
- Revisiting treatment-related cardiotoxicity in patients with malignant lymphoma-a review and prospects for the future.Frontiers in cardiovascular medicine · 2023Review
- Cell death regulation in myocardial toxicity induced by antineoplastic drugs.Frontiers in cell and developmental biology · 2023Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Observed only after administration of high doses, cardiotoxicity is the dose-limiting effect of cyclophosphamide (CY). We investigated the poorly understood cardiotoxic mechanisms of high-dose CY. A rat cardiac myocardial cell line, H9c2, was exposed to CY metabolized by S9 fraction of rat liver homogenate mixed with co-factors (CYS9). Cytotoxicity was then evaluated by 3-(4,5-dimethyl-2-thiazolyl)¬2,5-diphenyl¬2H-tetrazolium bromide (MTT) assay, lactate dehydrogenase release, production of reactive oxygen species (ROS), and incidence of apoptosis. We also investigated how the myocardial cellular effects of CYS9 were modified by acrolein scavenger N-acetylcysteine (NAC), antioxidant isorhamnetin (ISO), and CYP inhibitor β-ionone (BIO). Quantifying CY and CY metabolites by means of liquid chromatography coupled with electrospray tandem mass spectrometry, we assayed culture supernatants of CYS9 with and without candidate cardioprotectant agents. Assay results for MTT showed that treatment with CY (125-500 μM) did not induce cytotoxicity. CYS9, however, exhibited myocardial cytotoxicity when CY concentration was 250 μM or more. After 250 μM of CY was metabolized in S9 mix for 2 h, the concentration of CY was 73.6 ± 8.0 μM, 4-hydroxy-cyclophosphamide (HCY) 17.6 ± 4.3, o-carboxyethyl-phosphoramide (CEPM) 26.6 ± 5.3 μM, and acrolein 26.7 ± 2.5 μM. Inhibition of CYS9-induced cytotoxicity occurred with NAC, ISO, and BIO. When treated with ISO or BIO, metabolism of CY was significantly inhibited. Pre-treatment with NAC, however, did not inhibit the metabolism of CY: compared to control samples, we observed no difference in HCY, a significant increase of CEPM, and a significant decrease of acrolein. Furthermore, NAC pre-treatment did not affect intracellular amounts of ROS produced by CYS9. Since acrolein seems to be heavily implicated in the onset of cardiotoxicity, any competitive metabolic processing of CY that reduces its transformation to acrolein is likely to be an important mechanism for preventing cardiotoxicity.
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