title: Anti-tumorigenic action of 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b)pyran: evidence for involvement of GPR30/EGFR signaling pathway.
abstract: OBJECTIVE
  The aim of the present study was to investigate the effect of non-steroidal, pure antiestrogenic benzopyran derivative i.e., 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b)pyran (K-1) on the growth of human endometrial cancer cells in vivo and in vitro and to elucidate its mechanism of action.
  
  
  METHODS
  Cell proliferation was assayed by measuring the incorporation of 5'-bromo-2'-deoxyuridine in Ishikawa and primary endometrial cancer cells. The expression of proliferation and apoptotic markers was analyzed by immunoblotting. The effect of K-1 on GPR30-regulated proteins was analyzed by ELISA and by immunoblotting. Nude mice bearing subcutaneous implanted-Ishikawa tumors, were treated for 14days with K-1 (200μg/kg body weight/day/orally). The proliferation markers, GPR30-regulated proteins and apoptotic markers were analyzed by immunoblotting in tumor xenograft. The apoptotic effect of compound K-1 was determined by TUNEL assay.
  
  
  RESULTS
  Compound K-1 inhibited proliferation of endometrial adenocarcinoma cells and decreased the expression of proliferation markers. It caused apoptosis by increasing the expression of apoptotic markers (NOXA, PUMAα) and reducing the expression of p-CREB and BclxL. Compound interfered with GPR30-regulated-EGFR activation, decreased p-ERK, p-c-jun, c-fos, cyclinD1 and c-myc expression. Treatment of tumor-bearing mice with K-1 resulted in a significant decrease in tumor volume and weight. Decreased expression of p-ERK and its downstream molecules and increased expression of apoptotic markers were observed in tumor in K-1 treated animals.
  
  
  CONCLUSIONS
  Findings suggest the potent inhibitory effect of compound K-1 on endometrial cancer cellular growth (in-vitro) and on tumor size (in-vivo) which is mediated at least, in part, by interference with GPR30-signaling.
authors: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow-226001, UP, India.
authors: V
authors: V
authors: Chandra
authors: I
authors: I
authors: Fatima
authors: R
authors: R
authors: Saxena
authors: M K
authors: MK
authors: Hussain
authors: K
authors: K
authors: Hajela
authors: P
authors: P
authors: Sankhwar
authors: B G
authors: BG
authors: Roy
authors: S
authors: S
authors: Chandna
authors: A
authors: A
authors: Dwivedi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004334:Drug Administration Schedule; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D001578:Benzopyrans; D014408:Biomarkers, Tumor; C109584:GPER1 protein, human; C532507:GPER1 protein, mouse; D010880:Piperidines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C066625:2-(4-(2-piperidinoethoxy)phenyl)-3-(4-hydroxyphenyl)-2H-1-benzopyran; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors