Abstract
BackgroundDoxorubicin (DOX) is commonly used in the treatment of many types of cancers but its cardiotoxicity is limiting its clinical use. Beyond its anticoagulant action, enoxaparin (ENX), a low molecular weight heparin, has been shown to exert multiple pharmacological actions including antioxidant, anti-inflammatory and antiapoptotic effects. Therefore, the current study aimed to assess if ENX could ameliorate cardiotoxicity induced by DOX.MethodsTwenty-one adult male Wistar albino rats were randomly allocated into three groups (n = 7 each) of control, receiving 0.9% saline (i.p.), DOX, receiving 2.5 mg/kg of DOX (i.p.) thrice weekly; and DOX + ENX, receiving ENX (250 IU/kg/day i.p.) and a DOX dose equivalent to that of the DOX only group.ResultsDOX-induced cardiotoxicity was indicated by marked increases in cardiac troponin I (cTnI) and severe histological lesions, which significantly correlated with cardiotoxicity, oxidative stress, inflammation and apoptosis markers, compared to controls. DOX group also showed elevations in malondialdehyde (MDA), a marker of oxidative stress, and reductions in total antioxidant capacity (TAC). Cardiac inflammatory markers including tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) and caspase-3, an apoptotic marker, were also elevated in the DOX group. DOX, however, did not significantly alter brain natriuretic peptide (BNP) levels. ENX significantly attenuated, but not completely reversed, DOX-induced cardiotoxicity through lowering cTnI and improving cardiomyopathy histopathological scores as compared to the DOX group. ENX also decreased MDA, increased TAC of rats’ heart to levels relatively comparable to control. Significant reductions in TNF-α, IL-1β and caspase-3 were also observed following ENX treatment relative to the DOX only group.ConclusionsCollectively, these results describe a cardioprotective effect for ENX against DOX-induced cardiotoxicity which is likely facilitated via suppression of oxidative stress, inflammation and apoptosis.
Highlights
Doxorubicin (DOX) is commonly used in the treatment of many types of cancers but its cardiotoxicity is limiting its clinical use
The clinical effectiveness of DOX, is hindered by its most significant and dose-dependent cardiotoxicity [4, 5], with recent reports showing that DOX-induced cardiomyopathy being encountered more frequently due to growing survival rates in cancer patients treated by DOX-based chemotherapy [6]
Increased oxidative stress after DOX exposure leads to expression of transcription factor, nuclear factor kappa B cell (NF-Nuclear factor kappa B cell (κB)) and activation of nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, which, increases release of proinflammtory cytokines in the myocardium such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) [10, 11]
Summary
Doxorubicin (DOX) is commonly used in the treatment of many types of cancers but its cardiotoxicity is limiting its clinical use. Increased oxidative stress and continuous release of reactive oxygen species (ROS) via many contributing pathways are key elements to DOX-induced cardiotoxicity. These ROS can stimulate lipid peroxidation and subsequent oxidative damage to mitochondria and cell membranes of myocytes [9]. There is evidence which indicates that both extrinsic and intrinsic pathways of apoptosis are involved in the pathogenesis of DOX-Induced cardiotoxicity. Doxorubicin triggers apoptosis either directly by localizing to the mitochondria [12] and/or through oxidative stress and high accumulation of calcium in the cell, both are known to enhance the release of cytochrome C and stimulate the final step in caspase-3 induced programmed cell death [4, 8, 13]
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