Abstract
Doxorubicin, an anthracycline antibiotic, has been used as an anti-neoplastic drug for almost 60 years. However, the mechanism(s) by which anthracyclines cause irreversible myocardial injury remains unclear. In order to delineate possible molecular signals involved in the myocardial toxicity, we assessed candidate genes using mRNA expression profiling in the doxorubicin-treated rat cardiomyocyte H9c2 cell line. In the study, it was confirmed that myogenin, an important transcriptional factor for muscle terminal differentiation, was significantly reduced by doxorubicin in a dose-dependent manner using both RT-PCR and western blot analyses. Also, it was identified that the doxorubicin-reduced myogenin gene level could not be rescued by most cardio-protectants. Furthermore, it was demonstrated how the signaling of the decreased myogenin expression by doxorubicin was altered at the transcriptional, post-transcriptional and translational levels. Based on these findings, a working model was proposed for relieving doxorubicin-associated myocardial toxicity by down-regulating miR-328 expression and increasing voltage-gated calcium channel β1 expression, which is a repressor of myogenin gene regulation. In summary, this study provides several lines of evidence indicating that myogenin is the target for doxorubicin-induced cardio-toxicity and a novel therapeutic strategy for doxorubicin clinical applications based on the regulatory mechanisms of myogenin expression.
Highlights
Doxorubicin (DXR), an anthracycline antibiotic from Streptomyces peucetius, has been used as an anti-neoplastic drug for almost 60 years to treat several solid tumors and malignant hematological diseases [1]
A working model was proposed for relieving doxorubicin-associated myocardial toxicity by down-regulating micro RNA-328 (miR-328) expression and increasing voltage-gated calcium channel β1 expression, which is a repressor of myogenin gene regulation
We found that 1% FBS significantly induced troponin I and myogenin, and All-trans retinoic acid (atRA) further induced MLC 2v and Myo D1 (Figure 1b)
Summary
Doxorubicin (DXR), an anthracycline antibiotic from Streptomyces peucetius, has been used as an anti-neoplastic drug for almost 60 years to treat several solid tumors and malignant hematological diseases [1]. While topoisomerase 2β (Top 2β) is identified as the primary mediator for the anthracycline-induced toxic effects on cardiac myocytes [5, 6], the pathogenic mechanisms responsible for anthracycline cardio-toxicity have not been fully elucidated. Because no biomarker during DXR chemotherapy has been validated as a surrogate end point for clinically important cardiovascular disease, there is no effective approach that fully prevents or even treats DXR-associated cardio-toxicity. The measurement of cardiac enzymes or humoral factors, such as troponin I and T and B-type natriuretic peptide, are supplementary to detect early signs of DXR-induced cardio-toxicity, as they are not specific for DXR-induced damage. There remains an urgent need for methods to detect early signs of cardiac deterioration or subsequent cardiovascular events related to DXR treatment
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