The Protective Role of Resveratrol against Arsenic Trioxide-Induced Cardiotoxicity

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.

Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases

“…Resveratrol has also been shown to protect against arsenic trioxide-induced cardiotoxicity in mice and rats [276,277]. The protection against cisplatin and arsenic trioxide-induced cardiotoxicity has been attributed to the increase in the endogenous anti-oxidant enzymes activity namely, SOD, catalase, and glutathione peroxidase [270,277], in addition to activation of the anti-oxidant NRF2-heme oxygenase-1 pathway [276], suggesting the importance of the anti-oxidant properties of resveratrol in these models as well. Recently, an in vitro study has reported that resveratrol protects against sunitinib-induced hypertrophy in H9c2 cells [278].…”

“…Wang J et al have shown that resveratrol alleviated cisplatin-induced myocardial damage in a dose-dependent manner demonstrated by an improvement in histological appearance of the myocardium and normalization of markers of myocardial damage such as creatine kinase (CK) and lactate dehydrogenase (LDH) [270]. Resveratrol has also been shown to protect against arsenic trioxide-induced cardiotoxicity in mice and rats [276,277]. The protection against cisplatin and arsenic trioxide-induced cardiotoxicity has been attributed to the increase in the endogenous anti-oxidant enzymes activity namely, SOD, catalase, and glutathione peroxidase [270,277], in addition to activation of the anti-oxidant NRF2-heme oxygenase-1 pathway [276], suggesting the importance of the anti-oxidant properties of resveratrol in these models as well.…”

“…34 A C C E P T E D M A N U S C R I P T doses, one hour before arsenic trioxide Improved arsenic trioxideinduced myocardial damage [276] A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 43 Decreased oxidative/nitrative stress. [252] A C C E P T E D M A N U S C R I P T Dose-dependent increase in cerebral blood flow during task performance -pattern [153] A C C E P T E D M A N U S C R I P T Increase cerebral blood flow.…”

Arsenic and the Cardiovascular System

“…Furthermore, antioxidants such as resveratrol also possess similar effects as they were shown to prevent the down-regulation of Nrf2 and HO-1 in rats administered with ATO [125]. Resveratrol also decreased ROS generation and oxidative DNA damage.…”

Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells

“…Notably, we present for the first time a DNA microarray and proteomics analysis of the molecular signaling of arsenic trioxide‐induced apoptotic cell death in mesenchymal stem cells. Previous results ever showed that arsenic trioxide is able to provoke apoptotic death through DNA damage on cardiotoxicity (Zhang et al, ), A549 cells (Kryeziu et al, ), osteosarcoma (Nakamura et al, ), PLHC‐1 fish cells (Selvaraj et al, ), HL‐60 cells (Yedjou and Tchounwou, ; Yoda et al, ), melanoma (Balaz and Sedlak, ), and human HaCaT cells keratinocyte (Udensi et al, ). Our results indicated that arsenic trioxide is able to increase cell population of sub‐G1 phase in HUMSC and HMSC‐bm.…”