Mulberrin Confers Protection against Doxorubicin-Induced Cardiotoxicity via Regulating AKT Signaling Pathways in Mice

Abstract

Doxorubicin (DOX) is an antitumor anthracycline, but its clinical use was largely limited by its cardiac toxicity. DOX-induced oxidative damage and cardiomyocyte loss have been recognized as the potential causative mechanisms of this cardiac toxicity. Growing interests are raised on mulberrin (Mul) for its wide spectrum of biological activities, including antioxidative and anti-inflammatory properties. The aim of this study was to investigate the effect of Mul on DOX-induced heart injury and to clarify the underlying mechanism. Mice were given daily 60 mg/kg of Mul via gavage for 10 days. Mice received an intraperitoneal injection of DOX to mimic the model of DOX-related acute cardiac injury at the seventh day of Mul treatment. Mul-treated mice had an attenuated cardiac injured response and improved cardiac function after DOX injection. DOX-induced oxidative damage, inflammation accumulation, and myocardial apoptosis were largely attenuated by the treatment of Mul. Activated protein kinase B (AKT) activation was essential for the protective effects of Mul against DOX-induced cardiac toxicity, and AKT inactivation abolished Mul-mediated protective effects against DOX cardiotoxicity. In conclusion, Mul treatment attenuated DOX-induced cardiac toxicity via activation of the AKT signaling pathway. Mul might be a promising therapeutic agent against DOX-induced cardiac toxicity.

Everolimus Prevents Doxorubicin-Induced Apoptosis Through Autophagy, Mitophagy and AKT Activation in H9c2 Cardiomyocytes

“…This proposal is supported by the nding that MK-2206, a selective inhibitor of AKT, completely prevented the protective effects of EVL (Fig. 5c, d), as well as by previous reports revealing a protective role of the AKT signaling pathway against DOX cardiotoxicity [43][44][45].…”

α-Bisabolol, a Dietary Sesquiterpene, Attenuates Doxorubicin-Induced Acute Cardiotoxicity in Rats by Inhibiting Cellular Signaling Pathways, Nrf2/Keap-1/HO-1, Akt/mTOR/GSK-3β, NF-κB/p38/MAPK, and NLRP3 Inflammasomes Regulating Oxidative Stress and Inflammatory Cascades

“…Akt is the key signal transduction protein that phosphorylates several substrates and downstream effectors, including mTOR, and Akt/mTOR inactivation has also been shown to play a role in DOX-induced cardiotoxicity, whereas enhanced phosphorylation of Akt has been reported to prevent DOX-induced cardiotoxicity [ 61 , 62 ]. Akt inactivation also influences the expression of GSK-3β by triggering myocardial Nrf2 nuclear elimination and its cytoplasmic degradation in DOX-injected rats [ 63 ]. Consistent with previous studies [ 63 ], DOX triggered a reduction in the expression of phosphorylated AKT and phosphorylated GSK-3β, and mTOR, whereas BSB treatment reversed the expression of these proteins.…”

“…Akt inactivation also influences the expression of GSK-3β by triggering myocardial Nrf2 nuclear elimination and its cytoplasmic degradation in DOX-injected rats [ 63 ]. Consistent with previous studies [ 63 ], DOX triggered a reduction in the expression of phosphorylated AKT and phosphorylated GSK-3β, and mTOR, whereas BSB treatment reversed the expression of these proteins. The observations of the present study clearly reveal that BSB renders protective effects against oxidative stress and eventually cell death due to its potential to activate GSK-3β/Akt/mTOR signaling, which is in line with previous studies [ 63 ].…”