Daunomycin and other structurally related anthracyclines can cause myelosuppression and cardiomyopathy. We explored the possible mechanism(s) by which daunomycin (DAU) interacts with target sites in neoplastic hemopoietic cells and heart tissue. We observed that [3H(G)]DAU interacts selectively with mitochondrial hemoproteins isolated from K-562 cells and rat and bovine heart and forms relatively stable protein complexes. Isolation, purification, and chromatographic analysis of the mitochondrial components complexed with [3H(G)]DAU revealed that one of the major components involved is cytochrome c oxidase (COX). Both DAU and ADR caused a dose-dependent inhibition of COX activity in vitro, an event prevented by exogeneous hemin. The interaction of DAU with COX appears to occur via more than one site, one of which at least appears to be the prosthetic group of heme. Therefore, mitochondrial COX, a pivotal mitochondrial enzyme for cell respiration, may serve as a potential target site for DAU and other related anthracyclines.
Supported in part by a grant from the Greek National Drug Organization to A. S. T.