Abstract
Captopril (D‐3‐mercapto‐2‐methylpropanoyl‐L‐proli 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/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.
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Migdalof BH, Antonaccio MJ, McKinstry DN, Singhvi SM, Lan SJ, Egli P, Kripalani KJ: Captopril: Pharmacology, metabolism, and disposition. Drug Metab Rev 15: 841-869, 1984
Burris JF: The expanding role of angiotensin converting enzyme inhibitors in the management of hypertension. J Clin Pharmacol 35: 337-342, 1995
Garg R, Yusef S (for the Collaborative Group on ACE Inhibitor Trials): Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 273: 1450-1456, 1995
Pfeffer MA, Braunwald E, Moye LA et al.: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 327: 669-677, 1992
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 329: 1456-1462, 1993
Jackson WE, Holmes DL, Garg SK, Harris S, Chase HP: Angiotensin-converting enzyme inhibitor therapy and diabetic retinopathy. Ann Opthalmol 24: 99-103, 1992
Bauer HA, Lametschwandtner A, Steiner M, Bauer HC: Influence of angiotensin converting enzyme inhibitor (captopril) on kidney epithelial cells in vitro: Studies on potassium (86Rb) influx and cellular proliferation. Clin Chim Acta 187: 47-54, 1990.
Chen L, Re RN, Prakash O, Mondal D: Angiotensin-converting enzyme inhibition reduces neuroblastoma cell growth rate. Proc Soc Exp Biol Med 196: 280-283, 1991
Nguyen L, Ward WF, Ts'ao C, Molteni A: Captopril inhibits proliferation of human lung fibroblasts in culture: A potential antifibrotic mechanism. Proc Soc Exp Biol Med 205: 80-84, 1994
Reddy MK, Baskaran K, Molteni A: Inhibitors of angiotensin converting enzyme modulate mitosis and gene expression in pancreatic cancer cells. Proc Soc Exp Biol Med 210: 221-226, 1995
Nittler T, Stone M, Shroff O, McAuthur C, Veno P, Dobbs L, Brizio-Molteni L, Molteni A: Effect of captopril on the proliferation of a human salivary gland adenocarcinoma cell line (Abstract). FASEB 12: A811, 1998
Small Jr. W, Molteni A, Kim YT, Taylor JM, Chen Z, Ward WF: Captopril modulates hormone receptor concentration and inhibits proliferation of human mammary ductal carcinoma cells in culture. Breast Cancer Res Treat 44: 217-224, 1997
Zar JH: Biostatistical Analysis. Prentice-Hall, Englewood Cliffs, NJ, 1974, pp 121-181
Lipsky PE, Ziff M: The effect of D-penicillamine on mitogen-induced human lymphocyte proliferation: Synergistic inhibition by D-penicillamine and copper salts. J Immunol 120: 1006-1013, 1978.
Hammond WP, Miller JE, Starkebaum G, Zweernick HJ, Rosenthal AS, Dale DC: Suppression of in vitro granulocytopoiesis by captopril and penicillamine. Exp Hematol 16: 674-680, 1988
Held KD, Biaglow JE: Mechanisms for the oxygen radical-mediated toxicity of various thiol-containing compounds in cultured mammalian cells. Radiat Res 139: 15-23, 1994
Fernandex LA, Twickler J, Mead A: Neovascularization produced by angiotensin 2. J Lab Clin Med 105: 141-145, 1985
LaNoble FAC, Schreurs NHJS, Van Straaten JFM, Rogg H, Strijker-Boudier HA: Evidence for a novel angiotensin II receptor involved in chick embryo chorionallantoic membrane. Am J Physiol 246: R460-R463, 1993
Hernandex I, Cowley AW, Lanbard JH, Greene AS: Salt intake and angiotenin II alter microvessel density in the cremaster muscle of normal rats. Am J Physiol 263: H8664-H8667, 1992, 1996
Volpert OV, Ward WF, Lingen MW, Chesler L, Solt DB, Johnson MD, Molteni A, Polverini PJ, Bouck NP: Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats. J Clin Invest 98: 671-679, 1996
Roberts NA, Robinson PA: Copper chelates of antirheumatic and anti-inflammatory agents: Their superoxide dismutase-like activity and stability. Br J Rheumatol 24: 128-136, 1985
Reguli J, Misik V: Superoxide scavenging by thiol copper complex of captopril — an EPR spectroscopy study. Free Radical Res 22: 123-130, 1995
Jay D, Cuella A, Jay E: Superoxide dismutase activity of the captopril-iron complex. Mol Cell Biochem 146: 45-47, 1995
Keidar S, Kaplan M, Shapira C, Brook JG, Aviram M: Low density lipoprotein isolated from patients with essential hypertension exhibits increased propensity for oxidation and enhanced uptake by macrophages: A possible role for angiotensin II. Atherosclerosis 107: 71-84, 1994
Clearfield MB, Lee N, Armstrong L, DeFazio P, Kudchodkar BJ, Lacko AG: The effect of captopril on the oxidation of plasma lipoproteins. Pharmacol Toxicol 75: 218-221, 1994
Zieden B, Wuttge DM, Karlberg BE, Olsson AG: Effects of in vitro addition of captopril on copper-induced low density lipoprotein oxidation. Br J Clin Pharmacol 39: 201-203, 1995
de Cavanagh EM, Inserra F, Ferder L, Romano L, Ercole L, Fraga CG: Superoxide dismutase and glutathione peroxidase activities are increased by enalapril and captopril in mouse liver. FEBS Lett 36: 22-24, 1995
Sogaard P, Klausen IC, Rungby J, Faergeman O, Thygesen K: Lipoprotein(a) and oxygen free radicals in survivors of acute myocardial infarction: Effects of captopril. Cardiology 87: 18-22, 1996
Lapenna D, DeGioia S, Mezzetti A, Ciofani G, Di Ilio C, Cuccurullo F: The prooxidant properties of captopril. Biochem Pharmacol 50: 27-32, 1995
Clapperton M, Beswick PH, Abdullah I, Dargie HJ, Fisher AC, McMurray J: Effect of captopril, enalaprilat and mercaptopropionyl glycine (MPG) on the oxidative activity of human isolated neutrophils. Br J Clin Pharmacol 40: 31-35, 1995
Bagchi D, Prasad R, Das DK: Direct scavenging of free radicals by captopril, an angiotensin converting enzyme inhibitor. Biochem Biophys Res Comm 158: 52-57, 1989
Chopra M, Scott N, McMurray J, McLay J, Bridges A, Smith WE, Belch JJF: Captopril: A free radical scavenger. Br J Clin Pharmacol 27: 396-399, 1989
Mak IT, Freedman AM, Dickens BF, Weglicki WB: Protective effects of sulfhydryl-containing angiotensin converting enzyme inhibitors against free radical injury in endothelial cells. Biochem Pharmacol 40: 2169-2175, 1990
Aruoma OI, Akanmu D, Cecchini R, Halliwell B: Evaluation of the ability of the angiotensin-converting enzyme inhibitor captopril to scavenge reactive oxygen species. Chem-Biol Interactions 77: 303-314, 1991
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Small, W., Molteni, A., Kim, Y.T. et al. Mechanism of captopril toxicity to a human mammary ductal carcinoma cell line in the presence of copper. Breast Cancer Res Treat 55, 223–229 (1999). https://doi.org/10.1023/A:1006233521325
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DOI: https://doi.org/10.1023/A:1006233521325