Rutaecarpine Inhibits Doxorubicin-Induced Oxidative Stress and Apoptosis by Activating AKT Signaling Pathway

Abstract

Patients with cancer who receive doxorubicin (DOX) treatment can experience cardiac dysfunction, which can finally develop into heart failure. Oxidative stress is considered the most important mechanism for DOX-mediated cardiotoxicity. Rutaecarpine (Rut), a quinazolinocarboline alkaloid extracted from Evodia rutaecarpa was shown to have a protective effect on cardiac disease. The purpose of this study is to investigate the role of Rut in DOX-induced cardiotoxicity and explore the underlying mechanism. Intravenous injection of DOX (5 mg/kg, once a week) in mice for 4 weeks was used to establish the cardiotoxic model. Echocardiography and pathological staining analysis were used to detect the changes in structure and function in the heart. Western blot and real-time PCR analysis were used to detect the molecular changes. In this study, we found that DOX time-dependently decreased cardiac function with few systemic side effects. Rut inhibited DOX-induced cardiac fibrosis, reduction in heart size, and decrease in heart function. DOX-induced reduction in superoxide dismutase (SOD) and glutathione (GSH), enhancement of malondialdehyde (MDA) was inhibited by Rut administration. Meanwhile, Rut inhibited DOX-induced apoptosis in the heart. Importantly, we further found that Rut activated AKT or nuclear factor erythroid 2-related factor 2 (Nrf-2) which further upregulated the antioxidant enzymes such as heme oxygenase-1 (HO-1) and GSH cysteine ligase modulatory subunit (GCLM) expression. AKT inhibitor (AKTi) partially inhibited Nrf-2, HO-1, and GCLM expression and abolished the protective role of Rut in DOX-induced cardiotoxicity. In conclusion, this study identified Rut as a potential therapeutic agent for treating DOX-induced cardiotoxicity by activating AKT.

Clinical efficacy of Wenjing decoction in the treatment of ovulatory disorder infertility: A systematic review and meta-analysis

“…[ 38 ] Rutaecarpine (Rut), a quinazolinocarboline alkaloid extracted from Wuzhuyu was shown that it could ameliorate oxidative stress by improving SOD and glutathione (GSH), while inhibiting malondialdehyde (MDA). [ 39 ] Niu et al [ 40 ] showed that Chinese herbs Guizhi could improve oxidative stress induced by Chinese herbs Mahuang ( Ephedra sinica Stapf ). The steroidal saponins extract from Maidong and ingredients of Shengjiang have been proved to have antiinflammatory and antioxidant effects.…”

Research Progress on the Mechanism of Cardiotoxicity Caused by Doxorubicin and Its Treatment by Traditional Chinese Medicine

“…Nrf2 has long been recognised as an antioxidant and has a very high antioxidant capacity [16].DOX induces oxidative stress in cardiomyocytes by inhibiting the SIRT1/LKB1/AMPK/Nrf2 signalling pathway, HSP20/AKT/GSK3β/FYN/Nrf2 signalling pathway [17,18];inhibits autophagy by suppressing Nrf2 expression [19]; and induces cardiomyocyte apoptosis by inhibiting upstream of the PI3K / AKT signalling pathway and P38/MAPK to induce cardiomyocyte apoptosis [20,21]; and inducing iron death in cardiomyocytes by regulating the expression of p62 and thereby inhibiting the expression of Nrf2 [22], and SIRT1 may be one of the key components in the inhibition of Nrf2-induced iron death by DOX.The SIRT3/Nrf2 signalling pathway is involved in Doxorubicin-induced cardiomyocyte pyroptosis [23], and inhibition of the PI3K/AKT/Nrf2/p38/NF-κB p65 axis may be related to the pathway of Doxorubicin-induced cardiomyocyte inflammation [24]. Thus, it is evident that the pathogenesis of DIC is closely related to the inhibition of the Nrf2 signalling pathway, and therefore targeted activation of the Nrf2 signalling pathway is an important therapeutic strategy for DIC.…”

Nrf2: a dark horse in doxorubicin-induced cardiotoxicity

“…As stated in the section on oxidative stress, the phosphorylated PI3K/AKT signaling pathway plays a crucial role in enabling the separation of Nrf2 from Keap1 in order to complete nuclear translocation. In a recent study, doxorubicin was discovered to greatly enhance the expression of Caspase-3 and BCL-2 associated X (Bax), while decreasing the expression of B cell lymphoma-2 (Bcl-2) in cardiomyocytes, indicating that doxorubicin can really alter apoptosis in cardiomyocytes [ 120 ]. Further experiments revealed that doxorubicin decreased the expression of Nrf2 and its downstream HO-1, glutathione cysteine ligase modulatory subunit (GCLM), and p-AKT, and that pharmacological intervention reversed the alterations of these factors, and that the expression levels of Nrf2 and its downstream indicators were once again reversed after AKT inhibition.…”