Protective Effects of Oroxylin A against Doxorubicin‐Induced Cardiotoxicity via the Activation of Sirt1 in Mice

Abstract

Doxorubicin- (DOX-) related cardiac injury impairs the life quality of patients with cancer. This largely limited the clinical use of DOX. It is of great significance to find a novel strategy to reduce DOX-related cardiac injury. Oroxylin A (OA) has been identified to exert beneficial effects against inflammatory diseases and cancers. Here, we investigated whether OA could attenuate DOX-induced acute cardiotoxicity in mice. A single dose of DOX was used to induce acute cardiac injury in mice. To explore the protective effects, OA was administered to mice for ten days beginning from five days before DOX injection. The data in our study indicated that OA inhibited DOX-induced heart weight loss, reduction in cardiac function, and the elevation in myocardial injury markers. DOX injection resulted in increased oxidative damage, inflammation accumulation, and myocardial apoptosis in vivo and in vitro, and these pathological alterations were alleviated by treatment of OA. OA activated the sirtuin 1 (Sirt1) signaling pathway via the cAMP/protein kinase A, and its protective effects were blocked by Sirt1 deficiency. OA treatment did not affect the tumor-killing action of DOX in tumor-bearing mice. In conclusion, OA protected against DOX-related acute cardiac injury via the regulation of Sirt1.

Cariporide Attenuates Doxorubicin-Induced Cardiotoxicity in Rats by Inhibiting Oxidative Stress, Inflammation and Apoptosis Partly Through Regulation of Akt/GSK-3β and Sirt1 Signaling Pathway

“…Previous studies have revealed that Sirt1 was decreased in DOX treated heart or H9c2 cardiac cells ( Zhang S. et al, 2021 ; Liu Y. et al, 2021 ; Zhang WB. et al, 2021 ), and PI3K-Akt-GSK3β signaling pathway is required for Sirt1 induction by endoplasmic reticulum stress ( Koga et al, 2015 ), we then tested the protein expression of Sirt1.…”

The Role of Anthracyclines in Cardio-Oncology: Oxidative Stress, Inflammation, and Autophagy

“…The authors linked the protective effects exerted by OA administration to preserved levels of expression of sirtuin 1 (Sirt1), a critical deacetylase that is downregulated by DOX. They reported that OA is not protective in cardiac-restricted Sirt1 KO mice, showing that OA relies on Sirt1 activity to prevent acute DOX-induced cardiotoxicity [ 11 ].…”

Antidepressant-like activity of oroxylin A in mice models of depression: A behavioral and neurobiological characterization

“…Previous literatures have shown that oroxylin A inhibits inflammation by influencing the activity of many molecules (NLRP3 inflammasome, ERK, PI3K/AKT, Nrf2/ARE, NF-κB, etc.) ( Yao et al, 2014 ; Ye et al, 2014 ; Zhou et al, 2017 ; Zhang et al, 2021a ). Previous literatures have also indicated that oroxylin A not only inhibits H 2 O 2 -induced oxidative stress in PC12 cells but also prevents doxorubicin-induced cardiotoxicity by activating sirt1 in mice ( Han et al, 2017 ; Zhang et al, 2021 ).…”

“…( Yao et al, 2014 ; Ye et al, 2014 ; Zhou et al, 2017 ; Zhang et al, 2021a ). Previous literatures have also indicated that oroxylin A not only inhibits H 2 O 2 -induced oxidative stress in PC12 cells but also prevents doxorubicin-induced cardiotoxicity by activating sirt1 in mice ( Han et al, 2017 ; Zhang et al, 2021 ). It should be noticed that the pathogenesis of depression is accompanied with neuroinflammation, neuronal oxidative stress and sirt1 dysfunction ( Lu et al, 2018 ; Bhatt et al, 2020 ; Troubat et al, 2021 ).…”