MicroRNA‐34a‐5p as a promising early circulating preclinical biomarker of doxorubicin‐induced chronic cardiotoxicity

Abstract

Cardiotoxicity is a serious adverse effect of an anticancer drug, doxorubicin (DOX), which can occur within a year or decades after completion of therapy. The present study was designed to address a knowledge gap concerning a lack of circulating biomarkers capable of predicting the risk of cardiotoxicity induced by DOX. Profiling of 2083 microRNAs (miRNAs) in mouse plasma revealed 81 differentially expressed miRNAs 1 week after 6, 9, 12, 18, or 24 mg/kg total cumulative DOX doses (early‐onset model) or saline (SAL). Among these, the expression of seven miRNAs was altered prior to the onset of myocardial injury at 12 mg/kg and higher cumulative doses. The expression of only miR‐34a‐5p was significantly (false discovery rate [FDR] < 0.1) elevated at all total cumulative doses compared with concurrent SAL‐treated controls and showed a statistically significant dose‐related response. The trend in plasma miR‐34a‐5p expression levels during DOX exposures also correlated with a significant dose‐related increase in cardiac expression of miR‐34a‐5p in these mice. Administration of a cardioprotective drug, dexrazoxane, to mice before DOX treatment, significantly mitigated miR‐34a‐5p expression in both plasma and heart in conjunction with attenuation of cardiac pathology. This association between plasma and heart may suggest miR‐34a‐5p as a potential early circulating marker of early‐onset DOX cardiotoxicity. In addition, higher expression of miR‐34a‐5p (FDR < 0.1) in plasma and heart compared with SAL‐treated controls 24 weeks after 24 mg/kg total cumulative DOX dose, when cardiac function was altered in our recently established delayed‐onset cardiotoxicity model, indicated its potential as an early biomarker of delayed‐onset cardiotoxicity.

Abstract

Traditional technologies or cardiac disease markers have low sensitivity in detecting early signs of subclinical changes in hearts of cancer patients treated with doxorubicin (DOX). The present study identified miRNA‐34a‐5p as a potential early circulating biomarker of DOX cardiotoxicity in mice 1 week after receiving 6, 9, 12, 18, or 24 mg/kg total cumulative doses. Higher expression of miR‐34a‐5p in plasma at 24 weeks after receiving 24 mg/kg total dose suggested its potential as an early biomarker of delayed‐onset cardiotoxicity.