New aspects in probucol cardioprotection against doxorubicin-induced cardiotoxicity

El‐Demerdash, Ebtehal; Ali, Azza A.; Sayed‐Ahmed, Mohamed M.; Osman, Amira

doi:10.1007/s00280-003-0676-y

Cited by 27 publications

(11 citation statements)

References 24 publications

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“…We therefore surmised that probucol reduces oxidative damage by inhibiting p66Shc expression. Our results also support the findings of previous studies, which suggest that probucol is a cholesterol-lowering drug with antioxidant properties that protect against free radical-induced damage in a wide variety of scenarios, including doxorubicin-induced cardiotoxicity [7], HG-induced podocyte injury [49] and tubular epithelial cell injury [6]. The mechanism by which probucol protects against oxidative injury may involve increase in antioxidant gene mRNA expression and decrease in apoptosis via improving mitochondrial oxidative phosphorylation and energy production [1].…”

Section: Discussionsupporting

confidence: 90%

Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc

et al. 2017

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AimsProbucol is an anti-hyperlipidemic agent and a potent antioxidant drug that can delay progression of diabetic nephropathy (DN) and reverses renal oxidative stress in diabetic animal models; however, the mechanisms underlying these effects remain unclear. p66Shc is a newly recognized mediator of mitochondrial ROS production in renal cells under high-glucose (HG) ambience. We previously showed that p66Shc can serve as a biomarker for renal oxidative injury in DN patients and that p66Shc up-regulation is correlated with renal damage in vivo and in vitro. Here, we determined whether probucol ameliorates renal injury in DN by inhibiting p66Shc expression.ResultsWe found that the expression of SIRT1, Ac-H3 and p66Shc in kidneys of DN patients was altered. Also, probucol reduced the levels of serum creatinine, urine protein and LDL-c and attenuated renal oxidative injury and fibrosis in STZ induced diabetic mice. In addition, probucol reversed p-AMPK, SIRT1, Ac-H3 and p66Shc expression. Correlation analyses showed that p66Shc expression was correlated with p-AMPK and Sirt1 expression and severity of renal injury. In vitro pretreatment of HK-2 cells with p-AMPK and SIRT1 siRNA negated the beneficial effects of probucol. Furthermore, we noted that probucol activates p-AMPK and Sirt1 and inhibits p66shc mRNA transcription by facilitating the binding of Sirt1 to the p66Shc promoter and modulation of Ac-H3 expression in HK-2 cells under HG ambience.Innovation and conclusionOur results suggest for the first time that probucol ameliorates renal damage in DN by epigenetically suppressing p66Shc expression via the AMPK-SIRT1-AcH3 pathway.

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Section: Discussionsupporting

confidence: 90%

Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc

et al. 2017

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“…Results from several studies have indicated that increased intracellular oxygen-free radicals mediated by Dox induce inflammation (31). Therefore, the drugs that suppress this oxidative-inflammatory process have shown a potent protective effect in DIC (32,33).…”

Section: Discussionmentioning

confidence: 99%

Protective effect of cilostazol against doxorubicin-induced cardiomyopathy in mice

Koh

Heo

et al. 2015

Free Radical Biology and Medicine

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“…Interestingly, treatment with probucol completely prevented the increase in serum cardiac enzymes and lipid profile as well as TBARS induced by CP, suggesting that probucol may have potential protective effect against CP-induced cardiac damage. The protective effects of probucol against several forms of cardiomyopathies and congestive heart failure has been previously reported [33–35]. Also, lipid-lowering and antioxidant effects of probucol have been previously reported [33, 36].…”

Section: Discussionmentioning

confidence: 99%

“…The protective effects of probucol against several forms of cardiomyopathies and congestive heart failure has been previously reported [33–35]. Also, lipid-lowering and antioxidant effects of probucol have been previously reported [33, 36]. The contribution of oxidative stress and lipid peroxidation during development of CP induced cardiotoxicity have been recently reported [37, 38].…”

Section: Discussionmentioning

confidence: 99%

Probucol Attenuates Cyclophosphamide‐induced Oxidative Apoptosis, p53 and Bax Signal Expression in Rat Cardiac Tissues

Asiri

2010

Oxidative Medicine and Cellular Longevity

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Cyclophosphamide (CP) is a widely used drug in cancer chemotherapy and immunosuppression, which could cause toxicity of the normal cells due to its toxic metabolites. Probucol, a cholesterol-lowering drug, acts as potential inhibitor of DNA damage and shows to protect against doxorubicin-induced cardiomyopathy by enhancing the endogenous antioxidant system including glutathione peroxidase, catalase and superoxide dismutase. This study examined the possible protective effects of probucol, a lipid-lowering compound with strong antioxidant properties, against CPinduced cardiotoxicity. This objective could be achieved through studying the gene expression-based on the possible protective effects of probucol against CP-induced cardiac failure in rats. Adult male Wistar albino rats were assigned into four treatment groups: Animals in the first (control) and second (probucol) groups were injected intraperitoneally with corn oil and probucol (61 mg/kg/day), respectively, for two weeks. Animals in the third (CP) and fourth (probucol plus CP) groups were injected with the same doses of corn oil and probucol (61 mg/kg/day), respectively, for one week before and one week after a single dose of CP (200 mg/kg, I.P.). The p53, Bax, Bcl2 and oxidative genes signal expression were measured by real time PCR. CP-induced cardiotoxicity was clearly observed by a significant increase in serum creatine phosphokinase isoenzyme (CK-MB) (117%), lactate dehydrogenase (LDH) (64%), free (69%) and esterified cholesterol (42%) and triglyceride (69%) compared to control group. In cardiac tissues, CP significantly increases the mRNA expression levels of apoptotic genes, p53 with two-fold and Bax with 1.6-fold, and decreases the anti-apoptotic gene Bcl2 with 0.5-fold. Moreover, CP caused downregulation of antioxidant genes, glutathione peroxidase, catalase, and superoxide dismutase and increased the lipid peroxidation and decreased adenosine triphosphate (ATP) (40%) and ATP/ADP (44%) in cardiac tissues. Probucol pretreatment not only counteracted significantly the CP-induced increase in cardiac enzymes and apoptosis but also induced a significant increase in mRNA expression of antioxidant enzymes and improved ATP, ATP/ADP, glutathione (GSH) in cardiac tissues. In conclusion, data from the present study suggest that probucol prevents the development of CP-induced cardiotoxicity by a mechanism related, at least in part, to its ability to increase mRNA expression of antioxidant genes and to decrease apoptosis in cardiac tissues with the consequent improvement in mitochondrial oxidative phosphorylation and energy production.

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New aspects in probucol cardioprotection against doxorubicin-induced cardiotoxicity

Abstract: The present study demonstrated, for the first time, that probucol pretreatment alters the pharmacokinetics of DOX. Besides its antioxidant properties, the cardioprotective effect of probucol may be related to its enhancing action on the ATP/ADP ratio.

Cited by 27 publications

References 24 publications

Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc

Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc

Protective effect of cilostazol against doxorubicin-induced cardiomyopathy in mice

Probucol Attenuates Cyclophosphamide‐induced Oxidative Apoptosis, p53 and Bax Signal Expression in Rat Cardiac Tissues

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