Candidate early predictive plasma protein markers of doxorubicin-induced chronic cardiotoxicity in B6C3F1 mice


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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 B6C3F1 mice given a weekly intravenous dose of 3mg/kg DOX or saline (SAL) for 2, 3, 4, 6, or 8weeks (6, 9, 12, 18, or 24mg/kg cumulative DOX doses, respectively). Also, a group of mice received the cardio-protectant, dexrazoxane (DXZ; 60mg/kg; intraperitoneal) 30min 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 6mg/kg cumulative DOX dose, prior to the release of myocardial injury marker, cardiac troponin I at 12mg/kg and higher cumulative doses. These six proteins also remained significantly elevated following myocardial injury or pathology at 24mg/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.HIGHLIGHTSSignificant increase in plasma NOTCH1 prior to and after myocardial injury by doxorubicin in mice.Significant increase in plasma vWF level prior to and after myocardial injury by doxorubicin in mice.Dexrazoxane completely prevented formation of cardiac lesions in doxorubicin-treated mice.Dexrazoxane significantly attenuated increased plasma NOTCH1 level in doxorubicin-treated mice.Dexrazoxane significantly attenuated increased plasma vWF level in doxorubicin-treated mice.

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