1. Candidate early predictive plasma protein markers of doxorubicin-induced chronic cardiotoxicity in B6C3F 1 mice.
- Author
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Desai VG, Lee T, Moland CL, Vijay V, Han T, Lewis SM, Herman EH, and Fuscoe JC
- Subjects
- Administration, Intravenous, Animals, Biomarkers blood, Cardiotoxicity etiology, Cardiotoxicity prevention & control, Dexrazoxane administration & dosage, Doxorubicin administration & dosage, Heart drug effects, Male, Mice, Myocardium pathology, Protective Agents administration & dosage, Proteome analysis, Proteome drug effects, Proteomics, Receptor, Notch1 blood, Risk Assessment methods, von Willebrand Factor analysis, Antibiotics, Antineoplastic toxicity, Cardiotoxicity blood, Doxorubicin toxicity
- Abstract
Cardiotoxicity is a serious adverse effect of doxorubicin (DOX) treatment in cancer patients. Currently, there is a lack of sensitive biomarkers to predict the risk of DOX-induced cardiotoxicity. Using SOMAmer-based proteomic technology, 1129 proteins were profiled to identify potential early biomarkers of cardiotoxicity in plasma from male B6C3F
1 mice given a weekly intravenous dose of 3 mg/kg DOX or saline (SAL) for 2, 3, 4, 6, or 8 weeks (6, 9, 12, 18, or 24 mg/kg cumulative DOX doses, respectively). Also, a group of mice received the cardio-protectant, dexrazoxane (DXZ; 60 mg/kg; intraperitoneal) 30 min before a weekly DOX or SAL dose. Proteomic analysis in plasma collected a week after the last dose showed a significant ≥1.2-fold change in level of 18 proteins in DOX-treated mice compared to SAL-treated counterparts during 8-week exposure. Of these, neurogenic locus notch homolog protein 1 (NOTCH1), von Willebrand factor (vWF), mitochondrial glutamate carrier 2, Wnt inhibitory factor 1, legumain, and mannan-binding lectin serine protease 1 were increased in plasma at 6 mg/kg cumulative DOX dose, prior to the release of myocardial injury marker, cardiac troponin I at 12 mg/kg and higher cumulative doses. These six proteins also remained significantly elevated following myocardial injury or pathology at 24 mg/kg. Pretreatment of mice with DXZ significantly attenuated DOX-induced elevated levels of only NOTCH1 and vWF with mitigation of cardiotoxicity. This suggests NOTCH1 and vWF as candidate early biomarkers of DOX cardiotoxicity, which may help in addressing a clinically important question of identifying cancer patients at risk for cardiotoxicity., (Published by Elsevier Inc.)- Published
- 2019
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