Abstract
Adriamycin, a widely used anthracycline antibiotic in multiple chemotherapy regimens, has been challenged by the cardiotoxicity leading to fatal congestive heart failure in the worst condition. The present study demonstrated that Dihydromyricetin, a natural product extracted from ampelopsis grossedentat, exerted cardioprotective effect against the injury in Adriamycin-administrated ICR mice. Dihydromyricetin decreased ALT, LDH and CKMB levels in mice serum, causing a significant reduction in the toxic death triggered by Adriamycin. The protective effects were also indicated by the alleviation of abnormal electrocardiographic changes, the abrogation of proliferation arrest and apoptotic cell death in primary myocardial cells. Further study revealed that Dihydromyricetin-rescued loss of anti-apoptosis protein ARC provoked by Adriamycin was involved in the cardioprotection. Intriguingly, the anticancer activity of Adriamycin was not compromised upon the combination with Dihydromyricetin, as demonstrated by the enhanced anticancer effect achieved by Adriamycin plus Dihydromyricetin in human leukemia U937 cells and xenograft models, in a p53-dependent manner. These results collectively promised the potential value of Dihydromyricetin as a rational cardioprotective agent of Adriamycin, by protecting myocardial cells from apoptosis, while potentiating anticancer activities of Adriamycin, thus further increasing the therapeutic window of the latter one.
Highlights
Adriamycin (ADR), which belongs to anthracyclines, is one of the most widely prescribed and effective cytotoxic drugs used in oncology, involved in the treatment of many tumor types and associated with favorable clinical outcomes, including multiple myeloma, neuroblastoma, leukemia, sarcoma, lymphoma and so on [1, 2]
Dihydromyricetin protects against adriamycin-induced cardiotoxicity in vivo
In an attempt to further explore the underlying molecular mechanism by which DMY to exert cardioprotective activity, we mainly focused on the ARC protein, because (i) our preliminary data suggested that DMY could attenuate ADR-induced apoptosis, which probably owing to modulation of apoptotic related factors, (ii) ARC is an endogenous inhibitor of apoptosis which could protect the cells from stress-induced cell death, (iii) ARC is enriched in terminally differentiated cells and is recognized as a heart specific protein [27] (Figure 2)
Summary
Adriamycin (ADR), which belongs to anthracyclines, is one of the most widely prescribed and effective cytotoxic drugs used in oncology, involved in the treatment of many tumor types and associated with favorable clinical outcomes, including multiple myeloma, neuroblastoma, leukemia, sarcoma, lymphoma and so on [1, 2]. Increasing studies showed that myocardial toxicity manifested in its most severe form by fatal congestive heart failure (CHF) may occur either during the ADR therapy or months to years after the termination of the therapy, and the toxicity wound radically increased with the accumulation of ADR in a dosedependent manner [5]. In order to minimize ADR associated cardiotoxicity, several approaches could be considered: the rigorous cardiac monitoring, the use of anthracycline analogs with lower cardiotoxicity, and modifications of the program of administration [7]. The introduction of cardioprotective agents has been paid extensive attention
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