Protective Effect of Butylated Hydroxyanisole on Adriamycin-induced Cardiotoxicity

Abstract

Adriamycin has a wide spectrum of antitumour activity with dose-related cardiotoxicity as a major side effect. This cardiotoxicity has been suggested to result from the generation of oxygen free radicals. The objective of the present study was to investigate the influence of the antioxidant, butylated hydroxyanisole co-therapy on the cardiotoxicity of adriamycin, in-vivo. The aqueous solubility of butylated hydroxyanisole was enhanced by inclusion complex formation with hydroxypropyl-beta-cyclodextrin. The extent of drug-induced myocardial damage in rats was assessed using intravenous 111In-labelled antimyosin Fab and chronological changes in serum creatine kinase levels. There was a dose-related increase in myocardial antimyosin uptake in rats, which reached a plateau at an adriamycin dose of 10 mg kg-1. The antimyosin uptake at this dose (% dose g-1 = 0.1942 +/- 0.0150, n = 8) was significantly reduced by co-administration of butylated hydroxyanisole with adriamycin (10 mg kg-1 of each) to 0.1462 +/- 0.0116 (n = 5, P < 0.05). Assessment of cardiotoxicity in the rats was also performed by measuring serial changes in serum creatine kinase levels. Increasing doses of adriamycin caused an increase in serum creatine kinase levels with peak values obtained between 2 and 8 h after dosing. These values decreased upon co-administration of butylated hydroxyanisole with adriamycin at 10 mg kg-1, each and 30 mg kg-1 each by 29 and 41%, respectively. On the other hand, butylated hydroxyanisole did not inhibit the tumouricidal activity of adriamycin as investigated in-vitro using the NMU rat mammary adenocarcinoma cell-line. The significant reduction in anthracycline cardiotoxicity by butylated hydroxyanisole coadministration may result from its scavenging action on adriamycin-mediated free-radical formation or its enhancement of activity of enzymes involved in the metabolism of adriamycin.

Melatonin increased vitamin C and antioxidant enzyme values in the plasma,heart, liver, and kidney of Adriamycin-treated rats

“…NADPH-dependent reductase converts Adriamycin to semiquinone free radicals, which then leads to the generation of superoxide anion and hydroxyl radicals damaged to cellular lipids and lipoproteins. These radicals may play an important role in Adriamycin-induced cytotoxicity (Vora et al, 1996;Agopito et al, 2001;Lee et al, 2013). Thus, Adriamycininduced toxicity may contribute to a reduction in the antioxidant defense system in the heart and other tissues due to oxidative damage from these free radicals (Özdoğan et al, 2011).…”

“…Adriamycin is transformed to semiquinone free radicals by the NADPH-cytochrome P450 microsomal system. NADPH-dependent reductase converts Adriamycin to semiquinone free reactive radicals (Vora et al, 1996). Increasing of these radicals during biotransformation of Adriamycin may play a major role in Adriamycin-induced toxicity (Monti et al, 1996;Vora et al, 1996), causing oxidative stress of cellular components in cardiac (Kim et al, 2005;Özdoğan et al, 2011;Zang et al, 2013), hepatic (Aydoğan et al, 2013;Lee et al, 2013), and renal tissues (Hrenak et al, 2013;Escribano et al, 2014).…”

Glutathione S-transferase overexpression protects against anthracycline-induced H9C2 cell death

“…For example, in cultured cardiac myocytes, administration of the antioxidants amifostine, trolox, 5-aminosalicyclic acid, or ␣-phenyl-tert-butyl nitrone before AC exposure reduced indexes of oxidative stress and myocyte injury (12,13). In small animal models, the degree of AC-induced cardiac injury has also been reduced by pretreatment with exogenous antioxidants, including thymoquinone (3), butylated hydroxanisole (48), and the lipidlowering antioxidant probucol (27). Probucol-induced protection was accompanied by an increase in activity of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase (SOD) (41).…”

Captopril ameliorates myocardial and hematological toxicities induced by adriamycin

“…Many cytoprotective agents have been developed in order to counteract the functional disorders induced by adriamycin to make its use safer (10). Considerable efforts have been focused on using antioxidants, to protect the heart against adriamycin toxicity, however the results were not encourging since these cytoprotective agents only delay or decrease the development of cardio-myopathy and did not provide complete protection (11)(12).…”