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Inhibitory effects of anthracenedione antineoplastic agents on hepatic and cardiac lipid peroxidation
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 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.
Insights
Anthracenediones like mitoxantrone and ametantrone inhibit lipid peroxidation, unlike doxorubicin which enhances it. This suggests why anthracenediones have reduced cardiotoxicity compared to doxorubicin.
Area of Science:
- Biochemistry
- Pharmacology
- Toxicology
Background:
- Anthracyclines, such as doxorubicin, are effective chemotherapy agents but are associated with significant cardiotoxicity.
- Lipid peroxidation is a key mechanism implicated in drug-induced cellular damage, including cardiotoxicity.
Purpose of the Study:
- To compare the effects of mitoxantrone, ametantrone, and a monohydroxylated anthracenedione on lipid peroxidation in hepatic microsomes, cardiac sarcosomes, and cardiac mitochondria.
- To evaluate the potential of these anthracenediones to mitigate drug-induced lipid peroxidation and correlate this with their known cardiotoxicity profiles.
Main Methods:
- Assessed NADPH-dependent lipid peroxidation in rabbit hepatic microsomes and cardiac sarcosomes.
- Measured NADH-dependent lipid peroxidation in isolated rabbit cardiac mitochondria.
- Quantified malondialdehyde (MDA) production as an indicator of lipid peroxidation.
- Investigated the effects of anthracenediones on both basal and drug-stimulated (doxorubicin, nitrofurantoin, paraquat) lipid peroxidation.
Main Results:
- Mitoxantrone and ametantrone inhibited microsomal and mitochondrial lipid peroxidation in a concentration-dependent manner.
- Doxorubicin enhanced microsomal and mitochondrial lipid peroxidation, whereas anthracenediones inhibited it.
- Mitoxantrone and ametantrone protected against doxorubicin- and other drug-induced lipid peroxidation, with significant inhibition observed at low concentrations.
- Half-maximal inhibition of doxorubicin-stimulated microsomal lipid peroxidation was achieved by 4-6 microM mitoxantrone and ametantrone.
Conclusions:
- The ability of mitoxantrone and ametantrone to inhibit, rather than enhance, lipid peroxidation is a key difference from doxorubicin.
- This distinct effect on lipid peroxidation likely contributes to the reduced cardiotoxicity observed with ametantrone and mitoxantrone compared to doxorubicin and daunorubicin.