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Chemical Compound Review

Acolbifene     (2S)-3-(4-hydroxyphenyl)-4- methyl-2-[4-[2...

Synonyms: CHEMBL68055, SureCN406183, EM-652, AG-E-76853, CHEBI:203971, ...
 
 
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Disease relevance of Acolbifene

  • Our present findings indicate that EM-652, in addition to being the most potent antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues [1].
  • OBJECTIVE: EM-652 is a pure antiestrogen in human breast and uterine cancer cells that also reduces bone loss and plasma lipid levels in the rat [2].
  • DISCUSSION: EM-652 is an effective agent to prevent diet- and OVX-induced obesity and its associated cardiovascular risk factors such as insulin resistance [2].
  • These data imply that the classical electrophilic acolbifene quinone methide might contribute to the potential toxicity of acolbifene [3].
  • ANIMALS: Thirteen groups of eight Wistar female rats received oral EV (0.01 or 0.05 mg/kg of body weight daily), EM-652 (0.1, 1, or 5 mg/kg daily), or EV (0.05 mg/kg daily) and EM-652 (0.1, 1, or 5 mg/kg/daily) for 14 days [4].
 

High impact information on Acolbifene

  • EM-652 treatment does not decrease ER protein levels to a similar extent as ICI 182,780 treatment, and, in addition, EM-652 has no effect on ER mRNA levels [5].
  • Similarly, treatment with the antagonists 4-hydroxytamoxifen and EM-652 abolished all interactions between ERalpha and the SRC RIDs [6].
  • The present results demonstrate the importance of UGT1A isoforms, mainly UGT1A1, for EM-652 metabolism in humans [7].
  • EM-652 (SCH 57068) is a new orally active antiestrogen that demonstrates pure antagonistic effects in the mammary gland and endometrium [7].
  • Using hepatic microsomes from rat, monkey, and human, the formation of two EM-652 monoglucuronides at positions 4' and 7 was demonstrated by a liquid chromatographic tandem mass spectrometric method [7].
 

Chemical compound and disease context of Acolbifene

 

Biological context of Acolbifene

 

Anatomical context of Acolbifene

  • The present data show the poor or absent access of EM-652 to the brain, whereas the effects of estrogens are efficiently neutralized in the mammary gland and uterus [14].
  • In the present study, the vascular effects of EM-652 and E2 on the rat mesentery were investigated [15].
  • Moreover, ER alpha immunoreactivity remained constant in the hypothalamus after EM-652 treatment, whereas ER alpha became almost undetectable in the mammary gland and uterus [14].
  • EM-652 triggers NO release by human umbilical vein endothelial cells through nongenomic mechanisms, rapidly activating endothelial nitric oxide synthase (eNOS) via an ER-dependent sequential activation of MAPKs and PI3K/Akt pathways independently from gene transcription or protein synthesis [16].
  • EM-652 is also very effective in abrogating E2-stimulated ER alpha and ER beta trans-activation of the pS2 promoter in HeLa cells [17].
 

Associations of Acolbifene with other chemical compounds

  • From these studies, we conclude that the reason the pharmacology of EM-652 is similar to that of raloxifene is because they both fit the ER in the same manner, and their biology depends on an interaction of the antiestrogenic side chain with amino acid 351 [5].
  • As most of the cardioprotective actions of estrogen are exerted directly at the vascular level, we studied the effects of EM-652 on endothelial production of nitric oxide (NO) in vitro and in vivo [16].
  • EM-652 attenuated the vasoconstrictor responses induced by adrenergic agonists and endothelin-1 [15].
  • In addition, EM-652 blocks the E2-dependent activation of ER alpha and ER beta by the steroid hormone receptor coactivator-1 as well as the in vitro interaction between SRC-1 and the ligand-binding domains of both ERs [17].
  • CONCLUSIONS: Both ICI 182780 and EM-652 exhibited potent antioxidant activity, which could have important biological implications [18].
 

Gene context of Acolbifene

  • EM-652 inhibits Ras-induced transcriptional activity of ER alpha and ER beta and blocks SRC-1-stimulated activity of the two receptors [11].
  • EM-652 does not alter binding of ER alpha and ER beta to DNA [17].
  • Moreover, EM-652 increases eNOS protein levels during prolonged treatments [16].
  • In addition, PKC and MAPK inhibitors had no effect on the induction of TGFbeta3 promoter activity by the SERM EM-652 [19].
  • The present data demonstrate the high affinity and specificity of the new antiestrogen, EM-652, for the rat uterine estrogen receptor [20].
 

Analytical, diagnostic and therapeutic context of Acolbifene

  • In vivo studies have shown that EM-652 is primarily glucuronidated at the 7-hydroxy position in rats and that the metabolite is present in the plasma of female monkeys and human subjects after EM-800 (SCH 57050) or EM-652.HCl oral administration [7].
  • Potentially, E(2) + SCH 57068 could be combined for the treatment and prevention of breast cancer or as a novel hormone replacement therapy [12].
  • BACKGROUND: The objective was to determine if EM-652, a novel selective estrogen receptor modulator (SERM) having highly potent and pure antiestrogenic activity in the mammary gland could cause complete regression of the majority of human breast cancer xenografts in nude mice [9].

References

  1. 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. Gutman, M., Couillard, S., Roy, J., Labrie, F., Candas, B., Labrie, C. Int. J. Cancer (2002) [Pubmed]
  2. The estrogen antagonist EM-652 and dehydroepiandrosterone prevent diet- and ovariectomy-induced obesity. Lemieux, C., Picard, F., Labrie, F., Richard, D., Deshaies, Y. Obes. Res. (2003) [Pubmed]
  3. Bioactivation of the selective estrogen receptor modulator acolbifene to quinone methides. Liu, J., Liu, H., van Breemen, R.B., Thatcher, G.R., Bolton, J.L. Chem. Res. Toxicol. (2005) [Pubmed]
  4. 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. Bernardi, F., Stomati, M., Luisi, S., Pieri, M., Labrie, F., Riccardo Genazzani, A. Fertil. Steril. (2002) [Pubmed]
  5. The interaction of raloxifene and the active metabolite of the antiestrogen EM-800 (SC 5705) with the human estrogen receptor. Schafer, J.I., Liu, H., Tonetti, D.A., Jordan, V.C. Cancer Res. (1999) [Pubmed]
  6. Isoform-selective interactions between estrogen receptors and steroid receptor coactivators promoted by estradiol and ErbB-2 signaling in living cells. Bai, Y., Giguére, V. Mol. Endocrinol. (2003) [Pubmed]
  7. Glucuronidation of the nonsteroidal antiestrogen EM-652 (SCH 57068), by human and monkey steroid conjugating UDP-glucuronosyltransferase enzymes. Barbier, O., Albert, C., Martineau, I., Vallée, M., High, K., Labrie, F., Hum, D.W., Labrie, C., Bélanger, A. Mol. Pharmacol. (2001) [Pubmed]
  8. Characterization of the effects of the novel non-steroidal antiestrogen EM-800 on basal and estrogen-induced proliferation of T-47D, ZR-75-1 and MCF-7 human breast cancer cells in vitro. Simard, J., Labrie, C., Bélanger, A., Gauthier, S., Singh, S.M., Mérand, Y., Labrie, F. Int. J. Cancer (1997) [Pubmed]
  9. A novel pure SERM achieves complete regression of the majority of human breast cancer tumors in nude mice. Roy, J., Couillard, S., Gutman, M., Labrie, F. Breast Cancer Res. Treat. (2003) [Pubmed]
  10. Identification of novel proteins induced by estradiol, 4-hydroxytamoxifen and acolbifene in T47D breast cancer cells. Al-Dhaheri, M.H., Shah, Y.M., Basrur, V., Pind, S., Rowan, B.G. Steroids (2006) [Pubmed]
  11. EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium. Labrie, F., Labrie, C., Bélanger, A., Simard, J., Gauthier, S., Luu-The, V., Mérand, Y., Giguere, V., Candas, B., Luo, S., Martel, C., Singh, S.M., Fournier, M., Coquet, A., Richard, V., Charbonneau, R., Charpenet, G., Tremblay, A., Tremblay, G., Cusan, L., Veilleux, R. J. Steroid Biochem. Mol. Biol. (1999) [Pubmed]
  12. The selective estrogen receptor modulator SCH 57068 prevents bone loss, reduces serum cholesterol and blocks estrogen-induced uterine hypertrophy in ovariectomized rats. Goss, P.E., Qi, S., Cheung, A.M., Hu, H., Mendes, M., Pritzker, K.P. J. Steroid Biochem. Mol. Biol. (2004) [Pubmed]
  13. Synthesis and structure-activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution. Gauthier, S., Cloutier, J., Dory, Y.L., Favre, A., Mailhot, J., Ouellet, C., Schwerdtfeger, A., Mérand, Y., Martel, C., Simard, J., Labrie, F. Journal of enzyme inhibition and medicinal chemistry. (2005) [Pubmed]
  14. The combination of a novel selective estrogen receptor modulator with an estrogen protects the mammary gland and uterus in a rodent model: the future of postmenopausal women's health? Labrie, F., El-Alfy, M., Berger, L., Labrie, C., Martel, C., Bélanger, A., Candas, B., Pelletier, G. Endocrinology (2003) [Pubmed]
  15. Acute vascular effects of the selective estrogen receptor modulator EM-652 (SCH 57068) in the rat mesenteric vascular bed. Tatchum-Talom, R., Martel, C., Labrie, F., Marette, A. Cardiovasc. Res. (2003) [Pubmed]
  16. Genomic and nongenomic mechanisms of nitric oxide synthesis induction in human endothelial cells by a fourth-generation selective estrogen receptor modulator. Simoncini, T., Varone, G., Fornari, L., Mannella, P., Luisi, M., Labrie, F., Genazzani, A.R. Endocrinology (2002) [Pubmed]
  17. EM-800, a novel antiestrogen, acts as a pure antagonist of the transcriptional functions of estrogen receptors alpha and beta. Tremblay, A., Tremblay, G.B., Labrie, C., Labrie, F., Giguère, V. Endocrinology (1998) [Pubmed]
  18. Inhibition of low-density lipoprotein oxidation by the pure antiestrogens ICI 182780 and EM-652 (SCH 57068). Hermenegildo, C., García-Martínez, M.C., Tarín, J.J., Cano, A. Menopause (New York, N.Y.) (2002) [Pubmed]
  19. Requirement of Ras-dependent pathways for activation of the transforming growth factor beta3 promoter by estradiol. Lu, D., Giguère, V. Endocrinology (2001) [Pubmed]
  20. Binding characteristics of novel nonsteroidal antiestrogens to the rat uterine estrogen receptors. Martel, C., Provencher, L., Li, X., St Pierre, A., Leblanc, G., Gauthier, S., Mérand, Y., Labrie, F. J. Steroid Biochem. Mol. Biol. (1998) [Pubmed]
 
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