Mechanism of captopril toxicity to a human mammary ductal carcinoma cell line in the presence of copper.
Captopril (D-3-mercapto-2-methylpropanoyl-L-proline) 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/PR-negative 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 copper-loaded ceruloplasmin, captopril caused a dose-dependent reduction in cell number, thymidine incorporation and mitochondrial dehydrogenase activity. In contrast, iron salts and iron-saturated 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 copper-catalyzed oxidation of captopril, leading to the generation of H2O2 as the cytotoxin to this clinically important cell type.
Small
W
W
Department of Radiology, Northwestern University Medical School, Chicago 60611, USA.
Molteni
A
A
Kim
Y T
YT
Taylor
J M
JM
Ts'ao
C H
CH
Ward
W F
WF
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D001943:Breast Neoplasms / Q000473:pathology*; D002216:Captopril / Q000633:toxicity*; D018270:Carcinoma, Ductal, Breast / Q000473:pathology*; D003300:Copper / Q000502:physiology / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D017706:Lisinopril / Q000633:toxicity; D010396:Penicillamine / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000473:pathology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D003300:Copper; D002216:Captopril; D006861:Hydrogen Peroxide; D017706:Lisinopril; D010396:Penicillamine