Dihydromyricetin prevents cardiotoxicity and enhances anticancer activity induced by adriamycin

// Hong Zhu * , Peihua Luo * , Yingying Fu, Jincheng Wang, Jiabin Dai, Jinjin Shao, Xiaochun Yang, Linlin Chang, Qinjie Weng, Bo Yang, Qiaojun He Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China * these authors contributed equally to this work Correspondence to: Prof. Qiaojun He, e-mail: qiaojunhe@zju.edu.cn Keywords: Adriamycin, cardiotoxicity, Dihydromyricetin, ARC, anticancer Received: July 17, 2014      Accepted: August 28, 2014      Published: September 05, 2014 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.