Mechanism of captopril toxicity to a human mammary ductal carcinoma cell line in the presence of copper

Captopril (D3mercapto2methylpropanoylLproli ne) is an angiotensin converting enzyme (ACE) inhibitor, used widely in the treatment of hypertension and congestive heart failure. Captopril also inhibits proliferation of a variety of cell types, including several lacking ACE and renin acitvity. We have previously demonstrated that human mammary ductal carcinoma cells are among the cell types whose mitotic activity is inhibited by captopril. In those cells, captopril also reduces estrogen receptor (ER) and increases progesterone receptor (PR) concentrations. The present study evaluated the mechanism of captopril's antiproliferative action in an ER/PRnegative human mammary ductal carcinoma cell line, Hs578T. Cells grown in a 10% serum medium showed negligible changes in the presence of captopril alone. However, in the presence of subphysiologic concentrations of copper salts or copperloaded ceruloplasmin, captopril caused a dosedependent reduction in cell number, thymidine incorporation and mitochondrial dehydrogenase activity. In contrast, iron salts and ironsaturated transferrin had no effect on captopril activity. Catalase and horseradish peroxidase nullified the cytotoxic effects of captopril/Cu⁺⁺, whereas H₂O₂ mimicked those effects. These data are consistent with the notion of a coppercatalyzed oxidation of captopril, leading to the generation of H₂O₂ as the cytotoxin to this clinically important cell type.