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

Abstract

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.

Protective effect of N-acetylcysteine on cyclophosphamide-induced cardiotoxicity in rats

“…Data are presented as mean ± S.E., n = 6 * and # indicate significant change from control, and CP respectively at p ≤ 0.05 using ANOVA followed by Tukey-Kramer as a post ANOVA test. consistent with previous studies (Asiri, 2010;Nagi et al, 2011). CP is a cardiotoxic agent inducing a direct myocardial endothelial damage and destruction of myocardial cells.…”

Cardioprotective effects of Hypericum triquetrifolium Turra. against cyclophosphamide related cardiotoxicity in rats

“…This increase showed heart tissue damage, which are related with myocardial infarction, cardiac failure and myocarditis (Figure 2, 3). Similar to our study in many other studies [11,16,26] there was seen an increasing level of CK-MB when treated with CYP. Our biochemical data has been expressed in the same line with other studies which observed a significant increase in AST and CK-MB levels [25,29,32].…”

“…These may imply that overproduction of reactive oxygen species could be reduced by the HT, in the same line, other studies indicated a decrease in the antioxidantive enzyme activity is a consequence of raised oxidative stress in the heart tissue [34,37]. This results are consistent with numerous researches [11,16,38]. In 150 mg/kg CYP treated group the level of TOC increased, which indicated CYP-related oxidative stress and cardiac toxicity.…”

“…In the HT+CYP administered groups, a dose-dependent (specially in the 100 mg/kg HT+CYP group) decline in the cardiac biomarker's injuries (AST, CK-MB, MDA) and a signifiant increase in GSH level were observed. Paralel to the current study, Asiri et al [11] demonstrated that CYP significantly increased serum cardiac enzymes, CK-MB and AST while demonstrating an important decline in GSH. Similarly, Wei et al [36] resulted that CYP induces oxidative injuries in vital organs by increasing the MDA and declining GSH.…”

Hepatoprotective and antiapoptotic role of aged black garlic against hepatotoxicity induced by cyclophosphamide

“…Oxidative stress together with inflammation induces apoptosis (Alqahtani & Mahmoud, 2016). CP-induced apoptosis is mediated by oxidative stress (Asiri, 2010). Aged black garlic may act as an antimutagenic and protective agent against DNA damage via its antioxidant properties (Abdella & Gad, 2008).…”