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

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 138; pp. 123 - 131
• Main Authors: Fatima, I., Saxena, R., Kharkwal, G., Hussain, M.K., Yadav, N., Hajela, K., Sankhwar, P.L., Dwivedi, A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2013
• Subjects: Antineoplastic Agents - pharmacology; Benzopyran derivative; Benzopyrans - pharmacology; Cell Proliferation - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Endometrial cancer; Endometrial Neoplasms - metabolism; Estrogen receptor; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - agonists; Estrogen Receptor beta - metabolism; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Humans; Transcriptional activation; Tumor Cells, Cultured; Estrogen receptor; Endometrial cancer; Transcriptional activation; Benzopyran derivative
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2013.04.005

•Benzopyran compound (K-1) suppressed the endometrial cancer cellular growth.•It acts via ERβ agonism and exerts antagonistic effects on ERα.•It induced expression and activation of p21 and promotes ERα–β heterodimerization.•Dual action of benzopyran molecule may be of significant therapeutic value. 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) p21WAF-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.