INHIBITORY EFFECTS OF ANTHRACENEDIONE ANTI-NEOPLASTIC AGENTS ON HEPATIC AND CARDIAC LIPID-PEROXIDATION

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 226  (2) , 500-506
Abstract
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 .mu.M) 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 .mu.M anthracenedione. Mitochondria isolated from rabbit hearts supported NADH-dependent lipid peroxidation. Doxorubicin produced a maximal 3-fold enhancement of mitochondrial malondialdehyde production at 25 .mu.M. The anthracenediones comnpletely inhibited mitochondrial lipid peroxidation. Drug-stimulated lipid peroxidation was 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 and 6 .mu.M mitoxantrone and ametantrone, respectively. This effect was not limited to anthracycline-induced lipid peroxidation. Mitoxantrone and ametantrone protected against rat microsomal lipid peroxidation produced by nitrofurantoin, paraquat and doxorubicin, decreasing these rates by 80, 90 and 50%, respectively, at 10 .mu.M 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.