Ethanol-Extracted Cameroonian Propolis Counteracts Tamoxifen-Induced Endometrial Hyperplasia by Modulating Apoptosis and Proliferation-Regulating Proteins in the Ovaries of Intact Wistar Rats

Awounfack, Charline Florence; Zingue, Stéphane; Koumabas, Bruno; Tueche, Alain Brice; Tata, Charlotte Mungho; Fohouo, Fernand-Nestor Tchuenguem; Njamen, Dieudonné; Ndinteh, Derek Tantoh

doi:10.1155/2022/2684742

Cited by 2 publications

(2 citation statements)

References 37 publications

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“…Our study also veri ed that tamoxifen acted as a proestrogen agonist by causing the endometrium to appear thickened in immature rats, however, SCR-6852 decreased the uterine wet weight and endometrium thickness instead. This antiestrogenic effect of SCR-6852 was observed in Fulvestrant treatment in a previous report [34]. The above data demonstrated our compound SCR-6852 is a pure ER antagonist.…”

Section: Discussionsupporting

confidence: 83%

SCR-6852, an oral and highly brain-penetrating estrogen receptor degrader (SERD) effectively shrinks tumors both in intracranial and subcutaneous ER+ breast cancer models

Yang

Liu

et al. 2023

Preprint

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Background: Targeted estrogen receptor degradation has been approved to effectively treat ER + breast cancers. Due to the poor bioavailability of fulvestrant, the first generation of SERD, many efforts were made to develop oral SERDs. With the approval of Elacestrant, oral SERDs demonstrated superior efficacy than fulvestrant. However, due to the poor ability of known SERDs to penetrate the blood-brain barrier (BBB), breast cancer patients with brain metastasis cannot benefit from clinical SERDs.Methods The ER inhibitory effects were evaluated on ERα protein degradation, and target genes downregulation. And anti-proliferation activities were further determined in a panel of ER + breast cancer cell lines. The subcutaneous and intracranial ER + tumor models were used to evaluate the efficacy of anti-tumor effects. Brain penetrability was determined in multiple animal species.Results SCR-6852 is a novel SERD and currently is under early clinical evaluation. In vitro, studies demonstrated that it strongly induced both wildtype and mutant ERα degradation. It potently inhibited cell proliferation in a panel of ER + breast cancer cell lines, including the cell lines containing ESR1 mutations (Y537 and D538). Furthermore, SCR-6852 showed completely antagonistic activity on the ERɑ signal axis identified both in vitro and in vivo. Oral administration of SCR-6852 at 10mpk resulted in tumor shrinkage which was superior to Fulvestrant at 250mpk, Notably, in the intracranial tumor model, SCR-6852 effectively inhibited tumor growth and significantly prolonged mice survival, which correlated well with the high exposure in brains. In addition to mice, SCR-6852 also exhibited high brain penetrability in rats and dogs.Conclusions SCR-6852 is a best-in-class SERD with high potency in inducing ERα protein degradation and completely antagonistic activity on ERɑ signaling in vitro and in vivo. Due to the high brain penetrability, SCR-6852 could be used to treat breast patients with brain metastasis.

show abstract

Section: Discussionsupporting

confidence: 83%

SCR-6852, an oral and highly brain-penetrating estrogen receptor degrader (SERD) effectively shrinks tumors both in intracranial and subcutaneous ER+ breast cancer models

Yang

Liu

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Our study also verified that tamoxifen acted as a pro-estrogen agonist by causing the endometrium to appear thickened in immature rats, however, SCR-6852 decreased the uterine wet weight and endometrium thickness instead. This antiestrogenic effect of SCR-6852 was observed in Fulvestrant treatment in a previous report [35]. The above data demonstrated our compound SCR-6852 is a pure ER antagonist.…”

Section: Discussionsupporting

confidence: 83%

SCR-6852, an oral and highly brain-penetrating estrogen receptor degrader (SERD), effectively shrinks tumors both in intracranial and subcutaneous ER + breast cancer models

Yang

Liu

et al. 2023

Breast Cancer Res

View full text Add to dashboard Cite

Background Targeted estrogen receptor degradation has been approved to effectively treat ER + breast cancers. Due to the poor bioavailability of fulvestrant, the first generation of SERD, many efforts were made to develop oral SERDs. With the approval of Elacestrant, oral SERDs demonstrated superior efficacy than fulvestrant. However, due to the poor ability of known SERDs to penetrate the blood–brain barrier (BBB), breast cancer patients with brain metastasis cannot benefit from clinical SERDs. Methods The ER inhibitory effects were evaluated on ERα protein degradation, and target genes downregulation. And anti-proliferation activities were further determined in a panel of ER + breast cancer cell lines. The subcutaneous and intracranial ER + tumor models were used to evaluate the efficacy of anti-tumor effects. Brain penetrability was determined in multiple animal species. Results SCR-6852 is a novel SERD and currently is under early clinical evaluation. In vitro studies demonstrated that it strongly induced both wildtype and mutant ERα degradation. It potently inhibited cell proliferation in a panel of ER + breast cancer cell lines, including the cell lines containing ESR1 mutations (Y537 and D538). Furthermore, SCR-6852 exhibited pure antagonistic activities on the ERɑ signal axis identified both in vitro and in vivo. Oral administration of SCR-6852 at 10 mg/kg resulted in tumor shrinkage which was superior to Fulvestrant at 250 mg/kg, notably, in the intracranial tumor model, SCR-6852 effectively inhibited tumor growth and significantly prolonged mice survival, which correlated well with the high exposure in brains. In addition to mice, SCR-6852 also exhibited high brain penetrability in rats and dogs. Conclusions SCR-6852 is a novel SERD with high potency in inducing ERα protein degradation and pure antagonistic activity on ERɑ signaling in vitro and in vivo. Due to the high brain penetrability, SCR-6852 could be used to treat breast patients with brain metastasis.

show abstract

Ethanol-Extracted Cameroonian Propolis Counteracts Tamoxifen-Induced Endometrial Hyperplasia by Modulating Apoptosis and Proliferation-Regulating Proteins in the Ovaries of Intact Wistar Rats

Cited by 2 publications

References 37 publications

SCR-6852, an oral and highly brain-penetrating estrogen receptor degrader (SERD) effectively shrinks tumors both in intracranial and subcutaneous ER+ breast cancer models

SCR-6852, an oral and highly brain-penetrating estrogen receptor degrader (SERD) effectively shrinks tumors both in intracranial and subcutaneous ER+ breast cancer models

SCR-6852, an oral and highly brain-penetrating estrogen receptor degrader (SERD), effectively shrinks tumors both in intracranial and subcutaneous ER + breast cancer models

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