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.
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机译:三氧化二砷(As2O3)在急性早幼粒细胞白血病(APL)患者中显示出显着的抗癌活性。不幸的是,限制该有效剂对APL患者的应用是严重的心脏毒性。白藜芦醇,一种天然的食品来源的多酚化合物,以其抗氧化性能和保护心血管系统而闻名。但是尚不清楚白藜芦醇通过核因子红系2相关因子2(Nrf2)和血红素加氧酶1(HO-1)对心脏中As2O3的潜在作用。本研究评估了白藜芦醇和三氧化二砷预处理对大鼠氧化应激和心脏功能障碍的影响。在本研究中,白藜芦醇减少了As2O3诱导的活性氧生成,氧化DNA损伤和病理改变。此外,在用As2O3处理的大鼠中观察到心脏功能障碍参数,细胞内钙和砷蓄积,谷胱甘肽氧化还原比和cAMP缺乏水平。这些变化被白藜芦醇减弱。此外,白藜芦醇显着抑制了被As2O3下调的Nrf2和HO-1基因表达的下调,而白藜芦醇并未改变As2O3诱导的一氧化氮形成。因此,白藜芦醇对As2O3诱导的心脏毒性的保护作用是通过维持氧化还原稳态(Nrf2-HO-1途径)和促进砷外排而实现的。我们的研究结果表明与白藜芦醇共同给药,As 2 sub> O 3 sub>可能为APL提供新的治疗策略。
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