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 (earlyonset 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 SALtreated 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 earlyonset 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.

Circulating MicroRNA as Biomarkers of Anthracycline-Induced Cardiotoxicity

“…Most studies have focused on dynamic changes in cmiRNA after treatment. In all mouse studies, an increase in miR-34a levels was observed in both plasma 37 , 38 , 39 , 40 and myocardial tissue, suggesting a cardiac origin. 37 , 38 Similarly, rats exposed to repeated low doses of DOX showed increased miR-34a levels.…”

“… 39 , 40 In close association with miR-34a, a rise in miR-34c levels after DOX treatment was also described. 39 , 40 Additionally, an increase in miR-133a levels was observed after DOX treatment in both mice and rats. 37 , 38 , 42 , 43 In rats, an early rise in miR-1 and miR-133b levels was seen in the first 24 hours after a single high dose of anthracyclines.…”

“… 41 In mice, a dose-dependent rise in miR-34a levels appeared early, starting from day 6 after treatment, preceding any clinical signs of cardiotoxicity, whereas cTnT levels rose from day 7 onwards. 40 miR-34a levels remained elevated during treatment and persisted even after cessation of treatment. 39 , 40 In close association with miR-34a, a rise in miR-34c levels after DOX treatment was also described.…”

“… 40 miR-34a levels remained elevated during treatment and persisted even after cessation of treatment. 39 , 40 In close association with miR-34a, a rise in miR-34c levels after DOX treatment was also described. 39 , 40 Additionally, an increase in miR-133a levels was observed after DOX treatment in both mice and rats.…”

MicroRNA in the Diagnosis and Treatment of Doxorubicin-Induced Cardiotoxicity

“…Comparatively, the in vitro study showed that the expressions of miR-34a-5p, miR-34b-3p, and miR-34c-5p were all upregulated. Desai et al [ 132 ] explored the expression of miR-34a-5p by modeling early-onset and late-onset cardiotoxicity using DOX. After one week of treatment with DOX in the early-onset model, only the expression of miR-34a-5p was increased (false discovery rate (FDR) < 0.1), and there were statistically significant dose-related reactions with all the total cumulative doses.…”