The anti-proliferative effect of 2-[piperidinoethoxyphenyl]-3-[4- hydroxyphenyl]-2H-benzo(b) pyran is potentiated via induction of estrogen receptor beta and p21 in human endometrial adenocarcinoma cells

I. Fatima, R. Saxena, G. Kharkwal, M. K. Hussain, N. Yadav, K. Hajela, P. L. Sankhwar, A. Dwivedi

Research output: Contribution to journalArticle

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Abstract

In an effort to develop novel therapeutic agents for endometrial cancer, benzopyran derivatives synthesized at our institute display significant inhibitory activity on cellular growth in uterine cancer cells. The current study was undertaken to demonstrate and explore the estrogen receptor (ER) subtype mediated mechanism of action of benzopyran derivative 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b) pyran (K-1) in human endometrial cancer cells. K-1 competitively inhibited the estradiol binding to human ERα and ERβ and showed growth inhibitory activity in human endometrial Ishikawa, HEC1B and primary endometrial adenocarcinoma cells. Transient transactivation assays carried out in COS-1 cells have demonstrated the diminished ERα-ERE mediated- and induced the ERβ-ERE mediated-transactivation triggered by compound. It also induced ER-mediated transactivation of the cyclin-dependent kinase inhibitor (CDKI) p21 WAF-1 in both COS-1 cells and in Ishikawa cells. ERβ inducing effects of compound were blocked by ICI182,780. In endometrial adenocarcinoma cells, it induced ERβ and p21 expression significantly whereas the expression of fos, jun and ERα were significantly reduced. In addition, compound promoted ERα-β heterodimerization as observed in Ishikawa cells. These results demonstrate that the benzopyran compound suppressed the cellular growth via ERβ agonism, induction of p21 and via promoting the ERα-β heterodimerization, in addition to its antagonistic effects exerted on ERα, in human endometrial cancer cells. The study suggests that the dual action of benzopyran molecule may be of significant therapeutic value in ERα/β-positive cases of endometrial cancer.

Original languageEnglish (US)
Pages (from-to)123-131
Number of pages9
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume138
DOIs
StatePublished - Jun 12 2013

Fingerprint

Estrogen Receptor beta
Estrogen Receptors
Adenocarcinoma
Benzopyrans
Endometrial Neoplasms
Transcriptional Activation
COS Cells
Cells
2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran
Growth
Cyclin-Dependent Kinase Inhibitor p21
Derivatives
Uterine Neoplasms
Human Activities

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Medicine(all)
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Cite this

The anti-proliferative effect of 2-[piperidinoethoxyphenyl]-3-[4- hydroxyphenyl]-2H-benzo(b) pyran is potentiated via induction of estrogen receptor beta and p21 in human endometrial adenocarcinoma cells. / Fatima, I.; Saxena, R.; Kharkwal, G.; Hussain, M. K.; Yadav, N.; Hajela, K.; Sankhwar, P. L.; Dwivedi, A.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 138, 12.06.2013, p. 123-131.

Research output: Contribution to journalArticle

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abstract = "In an effort to develop novel therapeutic agents for endometrial cancer, benzopyran derivatives synthesized at our institute display significant inhibitory activity on cellular growth in uterine cancer cells. The current study was undertaken to demonstrate and explore the estrogen receptor (ER) subtype mediated mechanism of action of benzopyran derivative 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b) pyran (K-1) in human endometrial cancer cells. K-1 competitively inhibited the estradiol binding to human ERα and ERβ and showed growth inhibitory activity in human endometrial Ishikawa, HEC1B and primary endometrial adenocarcinoma cells. Transient transactivation assays carried out in COS-1 cells have demonstrated the diminished ERα-ERE mediated- and induced the ERβ-ERE mediated-transactivation triggered by compound. It also induced ER-mediated transactivation of the cyclin-dependent kinase inhibitor (CDKI) p21 WAF-1 in both COS-1 cells and in Ishikawa cells. ERβ inducing effects of compound were blocked by ICI182,780. In endometrial adenocarcinoma cells, it induced ERβ and p21 expression significantly whereas the expression of fos, jun and ERα were significantly reduced. In addition, compound promoted ERα-β heterodimerization as observed in Ishikawa cells. These results demonstrate that the benzopyran compound suppressed the cellular growth via ERβ agonism, induction of p21 and via promoting the ERα-β heterodimerization, in addition to its antagonistic effects exerted on ERα, in human endometrial cancer cells. The study suggests that the dual action of benzopyran molecule may be of significant therapeutic value in ERα/β-positive cases of endometrial cancer.",
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AU - Kharkwal, G.

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AU - Hajela, K.

AU - Sankhwar, P. L.

AU - Dwivedi, A.

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AB - In an effort to develop novel therapeutic agents for endometrial cancer, benzopyran derivatives synthesized at our institute display significant inhibitory activity on cellular growth in uterine cancer cells. The current study was undertaken to demonstrate and explore the estrogen receptor (ER) subtype mediated mechanism of action of benzopyran derivative 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b) pyran (K-1) in human endometrial cancer cells. K-1 competitively inhibited the estradiol binding to human ERα and ERβ and showed growth inhibitory activity in human endometrial Ishikawa, HEC1B and primary endometrial adenocarcinoma cells. Transient transactivation assays carried out in COS-1 cells have demonstrated the diminished ERα-ERE mediated- and induced the ERβ-ERE mediated-transactivation triggered by compound. It also induced ER-mediated transactivation of the cyclin-dependent kinase inhibitor (CDKI) p21 WAF-1 in both COS-1 cells and in Ishikawa cells. ERβ inducing effects of compound were blocked by ICI182,780. In endometrial adenocarcinoma cells, it induced ERβ and p21 expression significantly whereas the expression of fos, jun and ERα were significantly reduced. In addition, compound promoted ERα-β heterodimerization as observed in Ishikawa cells. These results demonstrate that the benzopyran compound suppressed the cellular growth via ERβ agonism, induction of p21 and via promoting the ERα-β heterodimerization, in addition to its antagonistic effects exerted on ERα, in human endometrial cancer cells. The study suggests that the dual action of benzopyran molecule may be of significant therapeutic value in ERα/β-positive cases of endometrial cancer.

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