Abstract
BackgroundLuteolin (LUT) is a flavonoid found in vegetables and fruits that has diverse functions. Doxorubicin (DOX) is an anthracycline antibiotic that is frequently used for the treatment of various cancers. Unfortunately, the clinical efficacy of DOX is limited by its dose-related cardiotoxicity. In this study, we aimed to investigate the potential mechanism through which LUT attenuates cardiotoxicity in vivo.MethodsWe evaluated the body weight, heart weight, electrocardiogram, and pathological changes before and after administration of LUT. Moreover, the effects of LUT (50 mg/kg in the low dose group, 100 mg/kg in the high dose group) on biochemical parameters (brain natriuretic peptide, creatine kinase MB, cardiac troponin T, and dehydrogenation of lactate enzyme) and oxidative stress parameters (malondialdehyde and superoxide dismutase) were studied in the sera of cardiotoxicity model rats. We also identified the apoptotic mediators whose expression was induced by LUT by quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR) evaluation. In addition, we used network analysis to predict DOX-induced cardiotoxicity and protection afforded by LUT. Western blotting was used to detect the expression of associated proteins.ResultsLUT significantly improved DOX-induced cardiotoxicity in a dose-dependent fashion. LUT ameliorated DOX-induced weight loss and heart weight changes, as well as changes in biochemical parameters and oxidative stress parameters in heart injury model rats. LUT’s protective effect was observed via regulation of the apoptotic markers Bcl-2, Bax, and caspase-3 mRNA and protein expression levels. Network analysis showed that the AKT/Bcl-2 signalling pathway was activated; specifically, the PH domain leucine-rich repeats protein phosphatase 1 (phlpp1) was involved in the AKT/Bcl-2 signal pathway. LUT inhibited the activity of phlpp1 leading to positive regulation of the AKT/Bcl-2 pathway, which attenuated doxorubicin-induced cardiotoxicity.ConclusionsThese results demonstrate that LUT exerted protective effects against DOX-induced cardiotoxicity in vivo by alleviating oxidative stress, suppressing phlpp1 activity, and activating the AKT/Bcl-2 signalling pathway.
Highlights
Doxorubicin (DOX, Fig. 1A) is widely used in the treatment of a variety of malignancies, in particular, solid tumours (Hu et al, 2018)
LUT significantly attenuated these effects (p < 0.05). These results demonstrated that LUT alleviated changes in heart weight induced by DOX
We identified that key target genes of LUT were AKT, CASP3, Bax, and Bcl, which play a key role in cardiotoxicity
Summary
Doxorubicin (DOX, Fig. 1A) is widely used in the treatment of a variety of malignancies, in particular, solid tumours (Hu et al, 2018). Dexrazoxane (DZR) is the only drug in clinical use that can protect against DOX-induced cardiotoxicity (Cvetković & Scott, 2005; Zhang et al, 2019). We aimed to investigate the potential mechanism through which LUT attenuates cardiotoxicity in vivo. We used network analysis to predict DOX-induced cardiotoxicity and protection afforded by LUT. LUT ameliorated DOX-induced weight loss and heart weight changes, as well as changes in biochemical parameters and oxidative stress parameters in heart injury model rats. LUT inhibited the activity of phlpp leading to positive regulation of the AKT/Bcl-2 pathway, which attenuated doxorubicin-induced cardiotoxicity. These results demonstrate that LUT exerted protective effects against DOX-induced cardiotoxicity in vivo by alleviating oxidative stress, suppressing phlpp activity, and activating the AKT/Bcl-2 signalling pathway
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