Mechanisms of beneficial effects of probucol in adriamycin cardiomyopathy

Probucol, a lipid-lowering drug, has been shown to offer protection against adriamycin-induced cardiomyopathy. In order to define the mechanism of this protection, we examined changes in antioxidants and lipid peroxidation in hearts as well as lipids in hearts and plasma from rats treated with either adriamycin or adriamycin and probucol with appropriate controls. Any potential free radical quenching as well as growth inhibitory effects of probucol were also examined using Chinese hamster ovary (CHO) cells in culture. In animal model, adriamycin caused a significant depression in glutathione peroxidase and increased plasma and cardiac lipids as well as lipid peroxidation. Probucol treatment modulated adriamycin-induced cardiomyopathic changes and increased glutathione peroxidase and superoxide dismutase activities. In the presence of adriamycin under hypoxic conditions, formation of adriamycin semiquinone radical was detected by ESR. The cell growth in these cultures was also inhibited by adriamycin in a dose-dependent manner. Probucol had no effect on adriamycin-induced growth inhibition as well as formation of semiquinone radicals. It is proposed that probucol protection against adriamycin cardiomyopathy is mediated by increased antioxidants and lipid-lowering without any effect on free radical production.     

Modulation of adriamycin-induced changes in serum free fatty acids,albumin and cardiac oxidative stress

Adriamycin-induced cardiomyopathic changes are prevented by combination therapy with probucol. These beneficial effects are suggested to be due to a combination of antioxidant as well as lipid-lowering effects of probucol. In the present study, we compared the effects of probucol (PROB) with that of lovastatin (LOV), a lipid-lowering drug, and trolox (TRO), an antioxidant, on adriamycin (ADR)-induced subchronic in vivo changes in serum free fatty acids (FFA), serum albumin and myocardial reduced (GSH) and oxidized (GSSG) glutathione in rats. ADR caused a significant increase in FFA, decrease in albumin, and an increase in FFA/albumin. PROB and LOV modulated the increases in FFA and FFA/albumin, while TRO was without any effect. ADR reduced myocardial GSH, increased GSSG and decreased GSH/GSSG. Only PROB caused significant improvement in GSH and normalized GSSG levels. It is suggested that these modulatory effects of probucol may also contribute in the beneficial effects of this drug against adriamycininduced cardiomyopathy and congestive heart failure.     

Adriamycin depresses in vivo and in vitro phosphatidylethanolamine N-methylation in rat heart sarcolemma

Adriamycin, an effective anticancer chemotherapeutic agent, causes an insidious and delayed cardiotoxicity. Different subcellular abnormalities including calcium transport changes in the sarcolemma (SL) as well as downregulation of the adrenergic system have been shown to be associated with the development of this cardiomyopathy. Since both of these activities are influenced by phospholipid methylation, effects of adriamycin on the three catalytic sites of SL phosphatidylethanolamine N-methyltransferase were examined. Rats were administered with a cumulative dose of adriamycin (15 mg/kg) over 2 weeks and examined after 3 weeks. Vehicle injected animals served as controls. Dyspnea, high mortality rate, ascites and decrease in aortic and left ventricular systolic pressure, as well as increase in left ventricular end diastolic pressure were seen in the adriamycin group. Myocardial cell damage typical of adriamycin cardiomyopathy, i.e. sarcotubular swelling, vacuolization and myofibrillar drop-out, was also apparent. Total methyl group incorporation into SL phosphatidylethanolamine using radiolabeled S-adenosyl-L-methionine as the donor was significantly depressed in the 3 week group at catalytic sites II and III. Decreased production of methylated intermediates, phosphatidyl-N-monomethylethanolamine and phosphatidyl-N,N-dimethylethanolamine as well as phosphatidylcholine (PC) was seen. Depression of phosphatidylethanolamine N-methylation was also noticed when SL, isolated from untreated hearts, was exposed in vitro to different concentrations (10, 100 and 1000 µM) of adriamycin. Inhibition of phosphatidylethanolamine N-methylation appears to be mediated by adriamycin-induced increase in the oxidative stress and may contribute in the pathogenesis of subcellular changes associated with this cardiomyopathy.     

Adriamycin-induced heart failure: mechanism and modulation

Adriamycin (doxorubicin) is one of the most effective chemotherapeutic agents against a variety of cancers, but its usefulness is seriously curtailed by the risk of developing heart failure. Available laboratory evidence suggests that an increase in oxidative stress, brought about by increased free radical production and decreased myocardial endogenous antioxidants, plays an important role in the pathogenesis of heart failure. Adriamycin-induced apoptosis and hyperlipidemia may also be involved in the process. Probucol, a lipid-lowering drug and an antioxidant, completely prevents the occurrence of heart failure by reducing oxidative stress as well as by the modulation of apoptis and high lipid concentrations. Thus, combined therapy with adriamycin and probucol has a high potential for optimizing the treatment of cancer patients.