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.
Highlights
Doxorubicin (DOX) is an effective chemotherapeutic drug that is widely used in treating several solid tumors and malignant hematologic diseases [1]
We found DOX time-dependently reduced cardiac function reflected by reduced left ventricular ejection fraction (LVEF), LV fractional shortening (LVFS), LV posterior wall (LVPW), and LV anterior wall (LVAW) during systole compared with vehicle-treated mice (Figure 1A)
Echocardiography showed DOX-treated mice developed heart failure reflected by reduced LVEF, LVFS, LVPW, and LVAW during systole compared with vehicle-treated mice, and these detrimental effects were dramatically mitigated by Rut administration (Figure 3A)
Summary
Doxorubicin (DOX) is an effective chemotherapeutic drug that is widely used in treating several solid tumors and malignant hematologic diseases [1]. Previous studies have proved that inhibition of oxidative stress dramatically alleviated DOX-induced cardiotoxicity in the heart [3]. Nrf-2 is an essential antioxidative gene that inhibits oxidative stress via upregulation of the intracellular antioxidant enzymes such as HO-1 and GCLM, which promote glutathione (GSH) generation [7]. Rutaecarpine (8,13dihydroindolo-(2′,3′:3,4)pyrido(2,1-b)quinazolin-5(7H)-one) is a quinazolinocarboline alkaloid that is extracted from the traditional Chinese herb Evodia rutaecarpa ( named Wu Zhu Yu) It exerts beneficial roles in treating several diseases including hypertension [12], cardiac hypertrophy [13], cardiac ischemia-reperfusion injury [14], diabetes [15], and tumor [16]. It has been reported that Rut protected hepatotoxicity by upregulating antioxidant enzymes through the Nrf-2/ARE pathway [18] and alleviated hypoxia-reoxygenation induced cardiomyocytes apoptosis through inhibiting NADPH oxidase expression [19]. Since Rut has been shown to activate PI3K/AKT signaling pathway [15], and PI3K/AKT was the upstream signal of Nrf-2 [20], in this study, we investigated whether Rut protected against DOX-induced cardiotoxicity
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