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

• Our data show that EM-800 and EM-652 are the most potent known antiestrogens in human breast cancer cells in vitro and that they are devoid of the estrogenic activity of OH-tamoxifen and droloxifene suggested by stimulation of cell growth in the absence of estrogens in ZR-75-1 and MCF-7 cells [8].
• CONCLUSIONS: The present data demonstrate that EM-652 is strongly cytotoxic or tumorocidal and not only cytostatic or tumorostatic in estrogen-sensitive breast cancer, thus changing the paradigm of a tumorostatic role of estrogen blockade established with tamoxifen [9].
• Identification of novel proteins induced by estradiol, 4-hydroxytamoxifen and acolbifene in T47D breast cancer cells [10].
• Most importantly, the antiestrogen hydroxytamoxifen has no inhibitory effect on the SRC-1-induced ER beta activity while the pure antiestrogen EM-652 completely abolishes this effect, thus strengthening the need to use pure antiestrogens in breast cancer therapy in order to control all known aspects of ER-regulated gene expression [11].

Biological context of Acolbifene

• Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease [1].
• As a pure antagonist of breast tumor development and growth, acolbifene does not stimulate endometrial tissue [3].
• Acolbifene could also induce DNA damage in the S30 breast cancer cell line [3].
• In summary, SCH 57068 adds to the positive effects of E(2) on bone and lipid metabolism but blocks the stimulatory effects of E(2) on the uterus [12].
• Synthesis and structure-activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution [13].

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