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  Acolbifene

Description of acolbifene: acolbifene is a substance being studied in the prevention of breast cancer in women at high risk of breast cancer. Acolbifene hydrochloride binds to estrogen receptors in the body and blocks the effects of estrogen in the breast. It is a type of selective estrogen receptor modulator (SERM).

Current developer:    EndoCeutics, Quebec City, Canada

Acolbifene, formerly known as EM-652, and SCH 57068, is a third generation SERM acting as pure antiestrogen. Acolbifene is also the orally active antiestrogen which is the most potent of the known antiestrogens and exerts pure antiestrogenic activity in the mammary gland and endometrium.

Acolbifene is currently in Phase II trials for the prevention of breast cancer sponsored by EndoCeutics, Quebec City, Canada.

EM-652 inhibits the AF-1 and AF-2 functions of both ERalpha and beta while the inhibitory action of OH-TAM is limited to AF-2. EM-652, thus, inhibits Ras-induced transcriptional activity and blocks SRC-1-stimulated activity of the two receptors. The absence of blockade of AF-1 by OH-TAM could explain why resistance develops to Tamoxifen treatment. Not only the development, but also the growth of established DMBA-induced mammary carcinoma is inhibited by treatment with EM-800, the prodrug of EM-652. EM-652 is the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro. When incubated with human Ishikawa endometrial carcinoma cells, EM-800 has no stimulatory effect on the estrogen-sensitive parameter alkaline phosphatase activity. When administered to ovariectomized animals, EM-800 prevents bone loss, and lowers serum cholesterol and triglyceride levels. EM-800 has shown benefits in women with breast cancer who had failed Tamoxifen. The above-summarized preclinical and clinical data clearly suggest the interest of studying this compounds in the neoadjuvant and adjuvant settings and, most importantly, for the prevention of breast and uterine cancer. (source: Labrie F, Labrie C, Bélanger A, Simard J, Giguère V, Tremblay A, Tremblay G. J Steroid Biochem Mol Biol. 2001 Dec;79(1-5):213-25.)

1: Liby K, Rendi M, Suh N, Royce DB, Risingsong R, Williams CR, Lamph W, Labrie F, Krajewski S, Xu X, Kim H, Brown P, Sporn MB. The combination of the rexinoid, LG100268, and a selective estrogen receptor modulator, either arzoxifene or acolbifene, synergizes in the prevention and treatment of mammary tumors in an estrogen receptor-negative model of breast cancer. Clin Cancer Res. 2006 Oct 1;12(19):5902-9. PubMed PMID: 17020999.

2: Al-Dhaheri MH, Shah YM, Basrur V, Pind S, Rowan BG. Identification of novel proteins induced by estradiol, 4-hydroxytamoxifen and acolbifene in T47D breast cancer cells. Steroids. 2006 Nov;71(11-12):966-78. Epub 2006 Sep 1. PubMed PMID: 16949628.

3: Lemieux C, Gélinas Y, Lalonde J, Labrie F, Richard D, Deshaies Y. Hypocholesterolemic action of the selective estrogen receptor modulator acolbifene in intact and ovariectomized rats with diet-induced hypercholesterolemia. Metabolism. 2006 May;55(5):605-13. PubMed PMID: 16631436.

4: Lemieux C, Gélinas Y, Lalonde J, Labrie F, Richard D, Deshaies Y. The selective estrogen receptor modulator acolbifene reduces cholesterolemia independently of its anorectic action in control and cholesterol-fed rats. J Nutr. 2005 Sep;135(9):2225-9. PubMed PMID: 16140902.

5: Berger L, El-Alfy M, Martel C, Labrie F. Effects of dehydroepiandrosterone, Premarin and Acolbifene on histomorphology and sex steroid receptors in the rat vagina. J Steroid Biochem Mol Biol. 2005 Jul;96(2):201-15. PubMed PMID: 15979306.

6: Gauthier S, Cloutier J, Dory YL, Favre A, Mailhot J, Ouellet C, Schwerdtfeger A, Mérand Y, Martel C, Simard J, Labrie F. Synthesis and structure-activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution. J Enzyme Inhib Med Chem. 2005 Apr;20(2):165-77. PubMed PMID: 15968821.

7: Lemieux C, Phaneuf D, Labrie F, Giguère V, Richard D, Deshaies Y. Estrogen receptor alpha-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene. Int J Obes (Lond). 2005 Oct;29(10):1236-44. PubMed PMID: 15925950.

8: Lemieux C, Gélinas Y, Lalonde J, Labrie F, Cianflone K, Deshaies Y. Hypolipidemic action of the SERM acolbifene is associated with decreased liver MTP and increased SR-BI and LDL receptors. J Lipid Res. 2005 Jun;46(6):1285-94. Epub 2005 Mar 1. PubMed PMID: 15741653.

9: Liu J, Liu H, van Breemen RB, Thatcher GR, Bolton JL. Bioactivation of the selective estrogen receptor modulator acolbifene to quinone methides. Chem Res Toxicol. 2005 Feb;18(2):174-82. PubMed PMID: 15720121.

10: Labrie F, Champagne P, Labrie C, Roy J, Laverdière J, Provencher L, Potvin M, Drolet Y, Pollak M, Panasci L, L'Espérance B, Dufresne J, Latreille J, Robert J, Samson B, Jolivet J, Yelle L, Cusan L, Diamond P, Candas B. Activity and safety of the antiestrogen EM-800, the orally active precursor of acolbifene, in tamoxifen-resistant breast cancer. J Clin Oncol. 2004 Mar 1;22(5):864-71. PubMed PMID: 14990642.

11: Gauthier S, Cloutier J, Dory YL, Favre A, Mailhot J, Ouellet C, Schwerdtfeger A, Mérand Y, Martel C, Simard J, Labrie F. Synthesis and structure-activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution. J Enzyme Inhib Med Chem. 2005 Apr;20(2):165-77. PubMed PMID: 15968821.

12: Lemieux C, Picard F, Labrie F, Richard D, Deshaies Y. The estrogen antagonist EM-652 and dehydroepiandrosterone prevent diet- and ovariectomy-induced obesity. Obes Res. 2003 Mar;11(3):477-90. PubMed PMID: 12634448.

13: Tatchum-Talom R, Martel C, Labrie F, Marette A. Acute vascular effects of the selective estrogen receptor modulator EM-652 (SCH 57068) in the rat mesenteric vascular bed. Cardiovasc Res. 2003 Feb;57(2):535-43. PubMed PMID: 12566126.

14: Hermenegildo C, García-Martínez MC, Tarín JJ, Cano A. Inhibition of low-density lipoprotein oxidation by the pure antiestrogens ICI 182780 and EM-652 (SCH 57068). Menopause. 2002 Nov-Dec;9(6):430-5. PubMed PMID: 12439102.

15: Bernardi F, Stomati M, Luisi S, Pieri M, Labrie F, Riccardo Genazzani A. Effects of the new generation selective estrogen receptor modulator EM-652 and oral administration of estradiol valerate on circulating, brain, and adrenal beta-endorphin and allopregnanolone levels in intact fertile and ovariectomized rats. Fertil Steril. 2002 May;77(5):1018-27. PubMed PMID: 12009361.

16: Gutman M, Couillard S, Roy J, Labrie F, Candas B, Labrie C. Comparison of the effects of EM-652 (SCH57068), tamoxifen, toremifene, droloxifene, idoxifene, GW-5638 and raloxifene on the growth of human ZR-75-1 breast tumors in nude mice. Int J Cancer. 2002 May 10;99(2):273-8. PubMed PMID: 11979444.

17: Labrie F, Labrie C, Bélanger A, Simard J, Giguère V, Tremblay A, Tremblay G. EM-652 (SCH57068), a pure SERM having complete antiestrogenic activity in the mammary gland and endometrium. J Steroid Biochem Mol Biol. 2001 Dec;79(1-5):213-25. Review. PubMed PMID: 11850228.

18: Pelletier G, El-Alfy M, Labrie C, Martel C, Labrie F. Effect of long-term treatment with the antiestrogen EM-652.HCl on pituitary estrogen receptor alpha and prolactin mRNA expression in intact, ovariectomized and gonadotropin-releasing hormone-treated female rats. Neuroendocrinology. 2001 Dec;74(6):367-74. PubMed PMID: 11752893.

19: Barbier O, Albert C, Martineau I, Vallée M, High K, Labrie F, Hum DW, Labrie C, Bélanger A. Glucuronidation of the nonsteroidal antiestrogen EM-652 (SCH 57068), by human and monkey steroid conjugating UDP-glucuronosyltransferase enzymes. Mol Pharmacol. 2001 Mar;59(3):636-45. PubMed PMID: 11179460.

20: Picard F, Deshaies Y, Lalonde J, Samson P, Labrie C, Bélanger A, Labrie F, Richard D. Effects of the estrogen antagonist EM-652.HCl on energy balance and lipid metabolism in ovariectomized rats. Int J Obes Relat Metab Disord. 2000 Jul;24(7):830-40. PubMed PMID: 10918529.

21: Labrie F, Labrie C, Bélanger A, Simard J, Gauthier S, Luu-The V, Mérand Y, Giguere V, Candas B, Luo S, Martel C, Singh SM, Fournier M, Coquet A, Richard V, Charbonneau R, Charpenet G, Tremblay A, Tremblay G, Cusan L, Veilleux R. EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):51-84. Review. PubMed PMID: 10418981.