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The wedelolactone derivative inhibits estrogen receptor-mediated breast, endometrial, and ovarian cancer cells growth.

Xu D, Lin TH, Yeh CR, Cheng MA, Chen LM, Chang C, Yeh S - Biomed Res Int (2014)

Bottom Line: Estrogen and estrogen receptor (ER)-mediated signaling pathways play important roles in the etiology and progression of human breast, endometrial, and ovarian cancers.Furthermore, our data indicate that BTB can modulate ER transactivation and suppress the expression of E2-mediated ER target genes (Cyclin D1, E2F1, and TERT) in the ER-positive MCF-7, Ishikawa, and SKOV-3 cells.Importantly, this BTB mediated inhibition of ER activity is selective since BTB does not suppress the activities of other nuclear receptors, including glucocorticoid receptor and progesterone receptor, suggesting that BTB functions as a selective ER signaling inhibitor with the potential to treat breast, endometrial, and ovarian cancers.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical and Life Sciences, Changzhou University, Changzhou, Jiangsu 213164, China ; George H. Whipple Laboratory for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.

ABSTRACT
Estrogen and estrogen receptor (ER)-mediated signaling pathways play important roles in the etiology and progression of human breast, endometrial, and ovarian cancers. Attenuating ER activities by natural products and their derivatives is a relatively practical strategy to control and reduce breast, endometrial, and ovarian cancer risk. Here, we found 3-butoxy-1,8,9-trihydroxy-6H-benzofuro[3,2-c]benzopyran-6-one (BTB), a new derivative of wedelolactone, could effectively inhibit the 17-estradiol (E2)-induced ER transactivation and suppress the growth of breast cancer as well as endometrial and ovarian cancer cells. Our results indicate that 2.5 μM BTB effectively suppresses ER-positive, but not ER-negative, breast, endometrial, and ovarian cancer cells. Furthermore, our data indicate that BTB can modulate ER transactivation and suppress the expression of E2-mediated ER target genes (Cyclin D1, E2F1, and TERT) in the ER-positive MCF-7, Ishikawa, and SKOV-3 cells. Importantly, this BTB mediated inhibition of ER activity is selective since BTB does not suppress the activities of other nuclear receptors, including glucocorticoid receptor and progesterone receptor, suggesting that BTB functions as a selective ER signaling inhibitor with the potential to treat breast, endometrial, and ovarian cancers.

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Related in: MedlinePlus

BTB selectively inhibits E2-mediated ER transactivation, moderately inhibits DHT-mediated AR transactivation, and fails to inhibit the PR and GR activity. (a) Chemical structures of wedelolactone and BTB. (b) and (c) BTB at 2.5, 5.0, and 10 μM concentrations can effectively inhibit the estrogen-induced ERα or ERβ transcriptional activity in HEK293 cells. (d) BTB moderately inhibits the androgen-induced AR transcriptional activity in HEK 293 cells. BTB at 5.0 μM concentration could not inhibit the AR transactivation, and 10 μM of BTB treatment started to show about 15–20% inhibition of the AR transactivation. (e)–(g) Inhibition of BTB on the E2-induced ER transcriptional activity in MCF-7, Ishikawa, and SKOV-3 cells. (h) and (i) Noeffects of BTB on the transcriptional activities of P4-induced PR and Dex-induced GR in Ishikawa cells. MMTV-Luc was used to determine the AR, PR, and GR mediated transactivation. ERE-Luc was used to assay ERα and ERβ mediated transactivation activities. Data represent mean ± SD collected from three independent experiments with duplication in each experiment.
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fig1: BTB selectively inhibits E2-mediated ER transactivation, moderately inhibits DHT-mediated AR transactivation, and fails to inhibit the PR and GR activity. (a) Chemical structures of wedelolactone and BTB. (b) and (c) BTB at 2.5, 5.0, and 10 μM concentrations can effectively inhibit the estrogen-induced ERα or ERβ transcriptional activity in HEK293 cells. (d) BTB moderately inhibits the androgen-induced AR transcriptional activity in HEK 293 cells. BTB at 5.0 μM concentration could not inhibit the AR transactivation, and 10 μM of BTB treatment started to show about 15–20% inhibition of the AR transactivation. (e)–(g) Inhibition of BTB on the E2-induced ER transcriptional activity in MCF-7, Ishikawa, and SKOV-3 cells. (h) and (i) Noeffects of BTB on the transcriptional activities of P4-induced PR and Dex-induced GR in Ishikawa cells. MMTV-Luc was used to determine the AR, PR, and GR mediated transactivation. ERE-Luc was used to assay ERα and ERβ mediated transactivation activities. Data represent mean ± SD collected from three independent experiments with duplication in each experiment.

Mentions: Traditional herb plants have a great importance due to their potential uses to treat diseases. Wedelia chinensis (Family: Asteraceae) has been used as a traditional Chinese medicine to treat septic shock, liver diseases, and viral infections [5]. This plant is a source of several secondary metabolites, such as flavonoids, phytosterols, and coumestans [6]. Coumestans represent an important class of natural oxygenated aromatic products, including wedelolactone. Wedelolactone (Figure 1(a)) is a naturally occurring furanocoumarin, which is an inhibitor of the IKK II [7], a kinase critical for the activation of NF-κB by mediating phosphorylation and degradation of IκBα. It also has many different bioactivities including antihepatotoxic, antihypertensive, antitumor, and antiphospholipase A2 properties, as well as being used as an antidote against snake venoms [8–11]. In addition to controlling NF-κB activity, wedelolactone is also known to possess estrogenic activity as it belongs to the coumestans family [12]. Recently, it was reported that wedelolactone inhibits growth of prostate and pituitary cancer cells [13–15].


The wedelolactone derivative inhibits estrogen receptor-mediated breast, endometrial, and ovarian cancer cells growth.

Xu D, Lin TH, Yeh CR, Cheng MA, Chen LM, Chang C, Yeh S - Biomed Res Int (2014)

BTB selectively inhibits E2-mediated ER transactivation, moderately inhibits DHT-mediated AR transactivation, and fails to inhibit the PR and GR activity. (a) Chemical structures of wedelolactone and BTB. (b) and (c) BTB at 2.5, 5.0, and 10 μM concentrations can effectively inhibit the estrogen-induced ERα or ERβ transcriptional activity in HEK293 cells. (d) BTB moderately inhibits the androgen-induced AR transcriptional activity in HEK 293 cells. BTB at 5.0 μM concentration could not inhibit the AR transactivation, and 10 μM of BTB treatment started to show about 15–20% inhibition of the AR transactivation. (e)–(g) Inhibition of BTB on the E2-induced ER transcriptional activity in MCF-7, Ishikawa, and SKOV-3 cells. (h) and (i) Noeffects of BTB on the transcriptional activities of P4-induced PR and Dex-induced GR in Ishikawa cells. MMTV-Luc was used to determine the AR, PR, and GR mediated transactivation. ERE-Luc was used to assay ERα and ERβ mediated transactivation activities. Data represent mean ± SD collected from three independent experiments with duplication in each experiment.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4157183&req=5

fig1: BTB selectively inhibits E2-mediated ER transactivation, moderately inhibits DHT-mediated AR transactivation, and fails to inhibit the PR and GR activity. (a) Chemical structures of wedelolactone and BTB. (b) and (c) BTB at 2.5, 5.0, and 10 μM concentrations can effectively inhibit the estrogen-induced ERα or ERβ transcriptional activity in HEK293 cells. (d) BTB moderately inhibits the androgen-induced AR transcriptional activity in HEK 293 cells. BTB at 5.0 μM concentration could not inhibit the AR transactivation, and 10 μM of BTB treatment started to show about 15–20% inhibition of the AR transactivation. (e)–(g) Inhibition of BTB on the E2-induced ER transcriptional activity in MCF-7, Ishikawa, and SKOV-3 cells. (h) and (i) Noeffects of BTB on the transcriptional activities of P4-induced PR and Dex-induced GR in Ishikawa cells. MMTV-Luc was used to determine the AR, PR, and GR mediated transactivation. ERE-Luc was used to assay ERα and ERβ mediated transactivation activities. Data represent mean ± SD collected from three independent experiments with duplication in each experiment.
Mentions: Traditional herb plants have a great importance due to their potential uses to treat diseases. Wedelia chinensis (Family: Asteraceae) has been used as a traditional Chinese medicine to treat septic shock, liver diseases, and viral infections [5]. This plant is a source of several secondary metabolites, such as flavonoids, phytosterols, and coumestans [6]. Coumestans represent an important class of natural oxygenated aromatic products, including wedelolactone. Wedelolactone (Figure 1(a)) is a naturally occurring furanocoumarin, which is an inhibitor of the IKK II [7], a kinase critical for the activation of NF-κB by mediating phosphorylation and degradation of IκBα. It also has many different bioactivities including antihepatotoxic, antihypertensive, antitumor, and antiphospholipase A2 properties, as well as being used as an antidote against snake venoms [8–11]. In addition to controlling NF-κB activity, wedelolactone is also known to possess estrogenic activity as it belongs to the coumestans family [12]. Recently, it was reported that wedelolactone inhibits growth of prostate and pituitary cancer cells [13–15].

Bottom Line: Estrogen and estrogen receptor (ER)-mediated signaling pathways play important roles in the etiology and progression of human breast, endometrial, and ovarian cancers.Furthermore, our data indicate that BTB can modulate ER transactivation and suppress the expression of E2-mediated ER target genes (Cyclin D1, E2F1, and TERT) in the ER-positive MCF-7, Ishikawa, and SKOV-3 cells.Importantly, this BTB mediated inhibition of ER activity is selective since BTB does not suppress the activities of other nuclear receptors, including glucocorticoid receptor and progesterone receptor, suggesting that BTB functions as a selective ER signaling inhibitor with the potential to treat breast, endometrial, and ovarian cancers.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical and Life Sciences, Changzhou University, Changzhou, Jiangsu 213164, China ; George H. Whipple Laboratory for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.

ABSTRACT
Estrogen and estrogen receptor (ER)-mediated signaling pathways play important roles in the etiology and progression of human breast, endometrial, and ovarian cancers. Attenuating ER activities by natural products and their derivatives is a relatively practical strategy to control and reduce breast, endometrial, and ovarian cancer risk. Here, we found 3-butoxy-1,8,9-trihydroxy-6H-benzofuro[3,2-c]benzopyran-6-one (BTB), a new derivative of wedelolactone, could effectively inhibit the 17-estradiol (E2)-induced ER transactivation and suppress the growth of breast cancer as well as endometrial and ovarian cancer cells. Our results indicate that 2.5 μM BTB effectively suppresses ER-positive, but not ER-negative, breast, endometrial, and ovarian cancer cells. Furthermore, our data indicate that BTB can modulate ER transactivation and suppress the expression of E2-mediated ER target genes (Cyclin D1, E2F1, and TERT) in the ER-positive MCF-7, Ishikawa, and SKOV-3 cells. Importantly, this BTB mediated inhibition of ER activity is selective since BTB does not suppress the activities of other nuclear receptors, including glucocorticoid receptor and progesterone receptor, suggesting that BTB functions as a selective ER signaling inhibitor with the potential to treat breast, endometrial, and ovarian cancers.

Show MeSH
Related in: MedlinePlus