title: Dihydromyricetin prevents cardiotoxicity and enhances anticancer activity induced by adriamycin.
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.
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Peihua
authors.initials: P
authors.lastname: Luo
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jincheng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jiabin
authors.initials: J
authors.lastname: Dai
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Shao
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Yang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Chang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Qinjie
authors.initials: Q
authors.lastname: Weng
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019610:Cytoprotection; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D044948:Flavonols / Q000494:pharmacology*; D018922:HL-60 Cells; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D020014:K562 Cells; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D003598:Cytoskeletal Proteins; D044948:Flavonols; D009419:Nerve Tissue Proteins; D020011:Protective Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C092069:activity regulated cytoskeletal-associated protein; D004317:Doxorubicin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C472036:dihydromyricetin