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.

Protective Effects of Dihydromyricetin against •OH-Induced Mesenchymal Stem Cells Damage and Mechanistic Chemistry

“…In the present study, Fenton's reagent (FeCl2 plus H2O2) was used to damage MSCs, and then the MTT assay was firstly used to evaluate the beneficial effect of DHM on •OH radical-treated MSCs: It must be emphasized that the structure of DHM has not been reported consistently in the literature. Zhu reported a structure with a double bond between the 2-and 3-positions of the DHM molecule [14]. Shen and colleagues incorrectly reported the stereo configuration of DHM [15].…”

“…As shown in Figure 3, DHM exhibited a protective effect against DNA damage in a concentration-dependent manner in vitro. Its protective effect on DNA is reported to be directly associated with its fast repairing DNA radical and ROS scavenging (antioxidant) effect [25], and may be partly responsible for its anticancer effect because cancer and aging are closely related to ‚OH radical-induced damage to cells and DNA [14,26,27].…”

“…It must be emphasized that the structure of DHM has not been reported consistently in the literature. Zhu reported a structure with a double bond between the 2-and 3-positions of the DHM molecule [14]. Shen and colleagues incorrectly reported the stereo configuration of DHM [15].…”

“…These structural inconsistencies and errors may lead to misunderstandings about some of the chemical moieties in the DHM molecule. For example, the structure drawn by Zhu is actually myricetin, not dihydromyricetin (DHM) and the 3-OH was wrongly identified as a phenolic -OH group [14]. Zhang even stated that the 3-OH along with other -OH groups and a -C=O played a critical role in antioxidant action of DHM [8].…”

Dihydromyricetin Protects against Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetic Mice

“…Over hundreds of years, DHM has been proven to have numerous pharmacological activities, including antioxidant, anti-inflammation, antihypertension, anticancer, hepatoprotection against alcohol intoxication, and antifatigue activities [5]. DHM can prevent adriamycin-induced cardiotoxicity by protecting myocardial cells from apoptosis and attenuate angiotensin II-induced rat cardiomyocyte hypertrophy in an NO-dependent manner [6, 7]. Moreover, DHM can mimic the effects of exercise-induced irisin secretion, which may be of great benefit to patients who suffer from metabolic diseases [8].…”