Tamoxifen Is a Potent Inhibitor of Cholesterol Esterification and Prevents the Formation of Foam Cells

  1. Philippe de Medina,
  2. Bruno L. Payré,
  3. José Bernad,
  4. Isabelle Bosser,
  5. Bernard Pipy,
  6. Sandrine Silvente-Poirot,
  7. Gilles Favre,
  8. Jean-Charles Faye and
  9. Marc Poirot
  1. Département Innovation Thérapeutique et Oncologie Moléculaire, Centre de Physiopathologie de Toulouse Purpan, Institut National de la Santé et de la Recherche Médicale Unité 563, Institut Claudius Regaud, Toulouse Cedex, France (P.D.M., B.L.P., S.S.P., G.F., J.C.F., M.P.); Laboratoire de la Signalisation et de la Différenciation des Macrophages, Institut Louis Bugnard, CHU Rangueil, Toulouse Cedex, France (J.B., B.P.); Centre de Microscopie Électronique Appliquée à la Biologie, Faculté de Médecine de Rangueil, Toulouse Cedex, France (B.L.P.); and Affichem, Ramonville-Saint-Agne, France (I.B.).
  1. Address correspondence to:
    Marc Poirot, Département Innovation Thérapeutique et Oncologie Moléculaire, Institut Claudius Regaud, INSERM U 563, CPTP, 20-24 rue du Pont Saint Pierre, 31052 Toulouse Cedex, France. E-mail: poirot{at}icr.fnclcc.fr

Abstract

Tamoxifen is a selective estrogen receptor modulator (SERM) used for the treatment and prevention of breast cancer. Tamoxifen has been reported to protect against the progression of coronary artery diseases in human and different atherosclerosis animal models by blocking the appearance of the atheromatous plaque. However, the molecular mechanism of this effect remains unknown. Acyl-CoA:cholesterol acyl transferase (ACAT) catalyzes the biosynthesis of cholesteryl esters, which are the major lipids found in the atheromatous plaque. In this paper we have tested whether ACAT might be inhibited by tamoxifen. We show, using molecular modeling, that tamoxifen displays three-dimensional structural homology with Sah 58-035 (3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide), a prototypical inhibitor of ACAT. We report that tamoxifen inhibits ACAT in a concentration-dependent manner on rat liver microsomal extract. We show that the presence on estrogen receptor ligands of a backbone isosteric to the diphenyl ethane backbone of Sah 58-035 constitutes a pharmacophore for ACAT inhibition. More importantly, tamoxifen was able to inhibit ACAT on intact macrophages stimulated with acetylated low-density lipoproteins and blocked the formation of foam cells, a step that precedes the formation of the atheromatous plaque. This work constitutes the first evidence that tamoxifen is an inhibitor of ACAT and foam cell formation at therapeutic doses and that this may account for its atheroprotective action.

Footnotes

  • This work was supported by the Institut National de la Recherche Médicale, a grant from the Association pour la Recherche sur le Cancer (ARC 5648), and a grant from the Caisse d'Assurance Maladie des Profession Libérales Provinces (Paris) and Affichem. P.D.M. was supported by the Ministère de la Recherche et de la Technologie.

  • DOI: 10.1124/jpet.103.060426.

  • ABBREVIATIONS: ACAT, acyl-CoA:cholesterol acyl transferase; ER, estrogen receptor; DPE, diphenylethane; DPM, diphenylmethane; RPM, rat peritoneal macrophage; LDL, low-density lipoprotein; AcLDL, acetylated low-density lipoprotein; Sah 58-035, 3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide; RU 39,411, 11β-[4-N,N-[diethylaminoethoxy]phenyl]-estra-1,3,5(10)-triene-3,17β-diol; RU 58,668, 11β-[[[(4,4,5,5,5,-pentafluoropentyl)sulfonyl]pentyloxy]phenyl]-estra-1,3,5(10)-triene-3,17β-diol; PBPE, 1-[2-(4-benzyl-phenoxy)-ethyl]-N-pyrrolidine hydrochloride; DMBPE, [2-(4-benzyl-phenoxy)-ethyl]-N,N-dimethyl-amine hydrochloride; TLC, thin-layer chromatography; ICI 182,780, Faslodex (fulvestrant); DMEM, Dulbecco's modified Eagle's medium; CI-628, nitromiphene citrate [α-(4-N-pyrrolidinethoxyl)phenyl-4-methoxy-α-nitrostilbene]); ICI 164,384, (N-n-butyl-N-methyl-11-[3,17β-di-hydroxyestra-1,3,5(10)-trien-7α-yl]-undecanamide.

    • Received September 24, 2003.
    • Accepted November 12, 2003.
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  1. doi: 10.1124/jpet.103.060426 JPET March 2004 vol. 308 no. 3 1165-1173
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