Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi‐1 expression

Abstract

Background and Purpose Doxorubicin‐based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin‐induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi‐1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin‐mediated protection against doxorubicin‐induced cardiotoxicity. Experimental Approach Effects of quercetin on doxorubicin‐induced cardiotoxicity was evaluated using H9c2 cardiomyocytes and C57BL/6 mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2 cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre‐treatment. Key Results In H9c2 cells, quercetin reduced doxorubicin‐induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double‐strand breaks. The quercetin‐mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53 and oxidase (p47 and Nox1) and by increased expression of Bcl‐2 and Bmi‐1. Bmi‐1 siRNA abolished the protective effect of quercetin against doxorubicin‐induced toxicity in H9c2 cells. Furthermore, quercetin protected mice from doxorubicin‐induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi‐1 and anti‐oxidative superoxide dismutase. Conclusions and Implications Our results demonstrate that quercetin decreased doxorubicin‐induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up‐regulation of Bmi‐1 expression. The findings presented in this study have potential applications in preventing doxorubicin‐induced cardiomyopathy.

Flavonoids ofCalligonum polygonoidesand their cytotoxicity

“…It was less active against HepG2 but more effective against MCF-7, compared with the standard compound doxorubicin. Quercetin was reported to be used in combination with doxorubicin to protect against doxorubicininduced cardiotoxicity and hepatotoxicity (Dong et al 2014). Although quercetin showed the highest cytotoxic effects among the tested flavonoids, quercetin effect at lower concentration, below (IC 50 ), exhibited a plateau as shown from its dose-response curve ( Figure 2).…”

Magnesium isoglycyrrhizinate ameliorates doxorubicin‑induced acute cardiac and hepatic toxicity via anti‑oxidant and anti‑apoptotic mechanisms in mice

“…However, even at clinically relevant doses, the therapeutic application of DOX is limited by systemic toxicity, including cardiotoxicity, hepatotoxicity and nephrotoxicity (13,14). DOX promotes reactive oxygen species (ROS), which mediates these organ toxicities (15)(16)(17). Cardiomyocytes are more vulnerable to attacks by oxygen free radicals since they are susceptible to ROS and contain lower levels of antioxidants, including glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) than other organs (16,18).…”

“…DOX promotes reactive oxygen species (ROS), which mediates these organ toxicities (15)(16)(17). Cardiomyocytes are more vulnerable to attacks by oxygen free radicals since they are susceptible to ROS and contain lower levels of antioxidants, including glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) than other organs (16,18). The liver is another organ that is particularly sensitive to DOX, due to its metabolism and detoxification activities.…”

Molecular Mechanisms Underlying the Nephrotoxicity of Cisplatin, Lead Acetate and Cyclosporine: Key Roles of Myc and Smad4

“…Taken together, we suggest that Recently, it has been determined that reduction of Pcgf4 can lead to apoptosis, senescence in tumor cells, and increased cell susceptibility to cytotoxic agents [46]. In addition, Pcgf4 can prevent cell toxicity in vitro and in vivo by reducing oxidative stress [47]. The Ybx1 is a key regulator of cell growth, apoptosis, drug resistance, DNA repair and transcription.…”