title: 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.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Saxena
authors.forename: Iram
authors.initials: I
authors.lastname: Fatima
authors.forename: Vishal
authors.initials: V
authors.lastname: Chandra
authors.forename: Chellakkan S
authors.initials: CS
authors.lastname: Blesson
authors.forename: Geetika
authors.initials: G
authors.lastname: Kharkwal
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Hussain
authors.forename: Kanchan
authors.initials: K
authors.lastname: Hajela
authors.forename: Bal G
authors.initials: BG
authors.lastname: Roy
authors.forename: Anila
authors.initials: A
authors.lastname: Dwivedi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D061986:MCF-7 Cells; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010880:Piperidines; D011960:Receptors, Estrogen; D018808:Transcription Factor AP-1; C066624:CDRI 85-287; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt
keywords: Breast cancer; Estrogen receptor; G2/M cell cycle progression; PI3K/Akt