Abstract
Arsenic trioxide (As2O3) shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Unfortunately, limiting the application of this effective agent to APL patients is severe cardiotoxicity. Resveratrol, the natural food-derived polyphenolic compound, is well known for its antioxidant properties and protects the cardiovascular system. But the potential role of resveratrol against As2O3 in heart via nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) is unclear. The present study evaluated the effects of pretreatment with resveratrol and As2O3 on oxidative stress and cardiac dysfunction in rat. In the present study, resveratrol decreased As2O3-induced reactive oxygen species generation, oxidative DNA damage, and pathological alterations. In addition, cardiac dysfunction parameters, intracellular calcium and arsenic accumulation, glutathione redox ratio, and cAMP deficiency levels were observed in As2O3-treated rats; these changes were attenuated by resveratrol. Furthermore, resveratrol significantly prohibited the downregulation of both Nrf2 and HO-1 gene expressions that were downregulated by As2O3, whereas resveratrol did not alter As2O3-induced nitric oxide formation. Thus, the protective role of resveratrol against As2O3-induced cardiotoxicity is implemented by the maintenance of redox homeostasis (Nrf2-HO-1 pathway) and facilitating arsenic efflux. Our findings suggest coadministration with resveratrol, and As2O3 might provide a novel therapeutic strategy for APL.
Highlights
High concentration of dietary exposure to arsenic and arsenic compounds is considered to increase the risk of human carcinogenesis [1]
Pretreatment of resveratrol resulted in a significant decrease in plasma lactate dehydrogenase (LDH), AST, creatine kinase (CK), and creatine kinase MB (CK-MB) release, 20.21%, 37.78%, 59.19%, and 49.88%, respectively, compared with that in the As2O3-treated group, whereas resveratrol alone did not show significant effect on LDH, AST, CK, and CK-MB activity
We investigated cardiac function associated with nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase-1 (HO-1) pathway and arsenic accumulation for the protection of resveratrol against As2O3-induced cardiac injury in Wistar rats in vivo
Summary
High concentration of dietary exposure to arsenic and arsenic compounds is considered to increase the risk of human carcinogenesis [1]. The use of these drugs is associated with cardiotoxicity (including a prolonged QT interval and prolonged action potential), torsades de pointes, and sudden cardiac death [2,3,4,5]. This may involve multiple mechanisms, including the generation of reactive oxygen species (ROS) in cardiomyocytes, oxidative DNA damage, and arsenic accumulation, [6,7,8]. It was reported that resveratrol could protect against cardiotoxicity in As2O3exposed mouse by the increase in the activities of antioxidant enzymes in the heart and antiapoptotic activity in H9c2 cardiomyocytes [15].
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