Benzopyran derivative CDRI-85/287 induces G2-M arrest in estrogen receptor-positive breast cancer cells via modulation of estrogen receptors α- and β-mediated signaling, in parallel to EGFR signaling and suppresses the growth of tumor xenograft.

Abstract

In an endeavor to develop novel and improved selective estrogen receptor modulators as anti-breast cancer agents, the benzopyran compounds have been synthesized and identified which act as potent anti-estrogen at uterine level. The present study evaluates the anti-tumor activity of 2-[piperidinoethoxyphenyl]-3-phenyl-2H-benzo(b)pyran (CDRI-85/287) and explores the mechanism of action with a view to describe its potential to inhibit proliferation in ER-positive breast cancer cells MCF-7 and T47D. The compound decreased the expression of ERα while increased the expression of ERβ thereby altering ERα/ERβ ratio in both cell lines. Although the compound showed low binding affinity to ERs, it acted as ERα antagonist and ERβ agonist in decreasing ERE- or AP-1-mediated transcriptional activation in these cells. Transactivation studies in ERα/β-transfected MDA-MB231 cells suggested that at cyclin D1 promoter, compound antagonized the action of ERα-mediated E2 response while acted as estrogen agonist via ERβ. Further, the compound led to decreased expression of ERα-dependent proliferation markers and ERβ-dependent cell cycle progression markers. The expression of cell cycle inhibitory protein p21 was increased leading to G2/M phase arrest. In parallel, compound also interfered with EGFR activation, caused inhibition of PI-3-K/Akt pathway and subsequent induction of apoptosis via intrinsic pathway. A significant reduction in tumor mass and volume was observed in 85/287-treated mice bearing MCF-7 xenograft. We conclude that compound 85/287 exhibits significant anti-tumor activity via modulation of genomic as well as non-genomic mechanisms involved in cellular growth and arrested the cells in G2 phase in both MCF-7 and T47D breast cancer cells. Study suggests that CDRI-85/287 may have therapeutic potential in ER-positive breast cancer.

• Authors: Ruchi Saxena, Iram Fatima, Vishal Chandra, Chellakkan S Blesson, Geetika Kharkwal, Mohammad K Hussain, Kanchan Hajela, Bal G Roy, Anila Dwivedi
• Journal: Steroids (Steroids) Vol. 78 Issue 11 Pg. 1071-86 (Nov 2013) ISSN: 1878-5867 [Electronic] United States
• PMID: 23891847 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Benzopyrans
• Biomarkers, Tumor
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Piperidines
• Receptors, Estrogen
• Transcription Factor AP-1
• CDRI 85-287
• Cyclin D1
• Epidermal Growth Factor
• Phosphatidylinositol 3-Kinases
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Agents (metabolism, pharmacology)
• Apoptosis (drug effects)
• Benzopyrans (metabolism, pharmacology)
• Binding, Competitive
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Cycle Checkpoints (drug effects)
• Cell Proliferation (drug effects)
• Cyclin D1 (genetics)
• Epidermal Growth Factor (pharmacology)
• ErbB Receptors (metabolism)
• Estrogen Receptor alpha (metabolism)
• Estrogen Receptor beta (metabolism)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• M Phase Cell Cycle Checkpoints (drug effects)
• MCF-7 Cells
• Mice
• Phosphatidylinositol 3-Kinases (metabolism)
• Piperidines (metabolism, pharmacology)
• Promoter Regions, Genetic (drug effects, genetics)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Estrogen (metabolism)
• Signal Transduction (drug effects)
• Transcription Factor AP-1 (metabolism)
• Transcriptional Activation (drug effects)
• Xenograft Model Antitumor Assays