The structural basis for anthracycline antibiotic stimulation of oxygen consumption by HL-60 cells and mitochondria.
The effects of anthracyclines on the stimulation of oxygen consumption in the presence of HL-60 cell sonicates, beef heart mitochondria and NADPH cytochrome c reductase were determined as a measure of oxygen radical production. Drug-induced oxygen radical formation in each of these systems was modulated by structural changes in the aglycone as well as in the amino sugar portion of the anthracycline molecule. Cytotoxic potency was not correlated with anthracycline-induced oxygen consumption, suggesting that net oxygen radical production was not the primary factor in tumor cell killing by anthracyclines. In contrast, available data on anthracycline cardiotoxicity appeared to correlate with the drug-induced stimulation of oxygen consumption by beef heart mitochondria, providing support for the premise that drug-induced oxygen radicals formed in the presence of mitochondrial flavoproteins are involved in the adverse effects of anthracyclines on the heart. Cyanomorpholinoadriamycin, an analogue which is 100 to 1000 times more potent than adriamycin (doxorubicin) as an antineoplastic agent, has been shown here and elsewhere to be equivalent to adriamycin in stimulating oxygen radical production by beef heart mitochondria and to produce similar cardiotoxicity at equimolar concentrations. Thus, it appears possible to separate the favorable antitumor activity of adriamycin from its unwanted cardiotoxicity by structural changes such as substitution of the antibiotic by a cyanomorpholino moiety.
D000818:Animals; D000903:Antibiotics, Antineoplastic; D002417:Cattle; D005609:Free Radicals; D066298:In Vitro Techniques; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D009279:Naphthacenes / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D005609:Free Radicals; D009279:Naphthacenes; D009251:NADPH-Ferrihemoprotein Reductase