Abstract
BackgroundDoxorubicin (DOX) is one of the most effective chemotherapeutic agents available; however, its use is limited by the risk of serious cardiotoxicity. Danshensu (DSS), an active ingredient in Salvia miltiorrhiza, has multiple cardioprotective effects, but the effect of DSS on DOX-induced cardiotoxicity has not been reported.ObjectivesPredicting the targets of DOX-induced cardiotoxicity and validating the protective effects and mechanisms of DSS.Methods(1) Using methods based on network pharmacology, DOX-induced cardiotoxicity was analyzed by data analysis, target prediction, PPI network construction and GO analysis. (2) The cardiotoxicity model was established by continuous intraperitoneal injection of 15 mg/kg of DOX into mice for 4 days and the protective effects and mechanism were evaluated by treatment with DSS.ResultsThe network pharmacology results indicate that CAT, SOD, GPX1, IL-6, TNF, BAX, BCL-2, and CASP3 play an important role in this process, and Keap1 is the main target of DOX-induced cardiac oxidative stress. Then, based on the relationship between Keap1 and Nrf2, the Keap1-Nrf2/NQO1 pathway was confirmed by animal experiments. In the animal experiments, by testing the above indicators, we found that DSS effectively reduced oxidative stress, inflammation, and apoptosis in the damaged heart, and significantly alleviated the prolonged QTc interval caused by DOX. Moreover, compared with the DOX group, DSS elevated Keap1 content and inhibited Nrf2, HO-1, and NQO1.ConclusionThe results of network pharmacology studies indicated that Keap1-Nrf2/NQO1 is an important pathway leading to DOX-induced cardiotoxicity, and the results of animal experiments showed that DSS could effectively exert anti-oxidative stress, anti-inflammatory and anti-apoptotic therapeutic effects on DOX-induced cardiotoxicity by regulating the expression of Keap1-Nrf2/NQO1.
Highlights
Doxorubicin (DOX), an anthracycline antibiotic, is the first-line drug for the clinical treatment of chemotherapy
We can see that superoxide dismutase (SOD), CAT, and GPX1 are related to oxidative stress, CASP3, BCL2, CASP1, and BCL2-associated X (BAX) are related to apoptosis, TNF and Interleukin- 6 (IL-6) are related to inflammation, and Kelch-like ECH-associated protein 1 (Keap1), Nuclear factor-carotenoid 2 (Nrf2), and NQO1 are targets of the Keap1-Nrf2/NQO1 pathway
We investigated the effects of DSS on oxidative stress, apoptosis, and inflammation production through pre-protection by establishing a DOX-induced cardiotoxicity model in mice, and verified whether these effects were related to the regulation of the Keap1-Nrf2/NQO1 pathway by measuring protein expression
Summary
Doxorubicin (DOX), an anthracycline antibiotic, is the first-line drug for the clinical treatment of chemotherapy. Mitochondria are the main organelle for ROS production, and once DOX enters the cardiomyocyte, nicotinamide adenine dinucleotide phosphate oxidase, and nitric oxide synthase in the mitochondria convert its quinine group to semiquinone. This semi-quinone reacts with O2− and is converted to H2O2 by superoxide dismutase (SOD). Severe oxidative stress can regulate B-cell lymphoma-2 (BCL-2) and BCL2-associated X (BAX) in mitochondria, and activate Caspase-3 (CASP3) to induce apoptosis [7]. Studies have confirmed that DOX-induced cardiotoxicity triggers arrhythmias, including prolonged QT interval, bradycardia and ST-segment elevation [8], cardiomyopathy, left ventricular insufficiency, and congestive heart failure [9]. Danshensu (DSS), an active ingredient in Salvia miltiorrhiza, has multiple cardioprotective effects, but the effect of DSS on DOX-induced cardiotoxicity has not been reported
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