Redox cycling in MCF-7 human breast cancer cells by antitumor agents based on mitozantrone

In a series of hydroxyethylaminoalkylaminoanthraquinones (AQ's) based on mitozantrone, 1-AQ (340%) and 1,8-AQ (137%) stimulated basal rate NADPH oxidation (72 + 18 pmol min-1 mg S9 protein-1) whilst 1,4-AQ, 1,5-AQ and mitozantrone had no effect. A similar trend was observed for O2.- generation (measured as nmol acet. cyt c reduction min-1 mg protein-1) by these compounds in MCF-7 S9 fraction: 1-AQ (9.5) and 1,8-AQ (7.9), whilst 1,5-AQ, 1,4-AQ and mitozantrone showed no significant effect. All the AQ's including mitozantrone were cytotoxic to MCF-7 cells in a dose dependent manner with EC50 values as follows: 1-AQ (0.01 micron) greater than doxorubicin (0.4 microM) greater than mitozantrone (0.6 microM) greater than 1,8-AQ (2.0 microM) greater than 1,5-AQ (4.0 microM) greater than 1,4-AQ (8.0 microM). Thus the redox active AQ's were also the most cytotoxic. Mitozantrone however was not redox active but was more cytotoxic than all but 1-AQ hence it would appear that factors other than free radical generation contribute to the antitumor activity of this group of compounds.