Inhibitory effects of anthracenedione antineoplastic agents on hepatic and cardiac lipid peroxidation.
The effects of mitoxantrone, ametantrone and a monohydroxylated anthracenedione on hepatic microsomal, cardiac sarcosomal and cardiac mitochondrial lipid peroxidation were examined and compared with those of doxorubicin and daunorubicin. Rabbit microsomal NADPH-dependent lipid peroxidation was inhibited by the anthracenediones in a concentration-dependent manner, whereas doxorubicin caused a concentration-dependent enhancement of peroxidation. Mitoxantrone and ametantrone (200 microM) completely inhibited microsomal malondialdehyde production while an identical concentration of doxorubicin caused a 2.5-fold stimulation. Rabbit cardiac sarcosomal NADPH-dependent malondialdehyde production was also abolished by 100 microM anthracenedione. Mitochondria isolated from rabbit hearts were found to support NADH-dependent lipid peroxidation. Doxorubicin produced a maximal 3-fold enhancement of mitochondrial malondialdehyde production at 25 microM. The anthracenediones however, completely inhibited mitochondrial lipid peroxidation Drug-stimulated lipid peroxidation was also effectively diminished by mitoxantrone and ametantrone in a concentration-dependent manner. Half-maximal inhibition of doxorubicin-stimulated rabbit microsomal malondialdehyde production was achieved by 4 anal 6 microM mitoxantrone and ametantrone, respectively. Furthermore this effect was not limited to anthracycline-induced lipid peroxidation. Mitoxantrone and ametantrone also protected against rat microsomal lipid peroxidation produced by nitrofurantoin, paraquat and doxorubicin, decreasing these rates by 80, 90, and 50%, respectively, at 10 microM anthracenedione. The relative inability of the anthracenediones to stimulate lipid peroxidation is consistent with the diminished cardiotoxicity of ametantrone and mitoxantrone relative to doxorubicin and daunorubicin.[1]References
- Inhibitory effects of anthracenedione antineoplastic agents on hepatic and cardiac lipid peroxidation. Kharasch, E.D., Novak, R.F. J. Pharmacol. Exp. Ther. (1983) [Pubmed]
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