title: Inhibition of leiomyoma cell proliferation in vitro by genistein and the protein tyrosine kinase inhibitor TKS050.
abstract: OBJECTIVE
  To determine the potency of TKS050, a new epidermal growth factor receptor (EGFR) inhibitor and genistein, a naturally occurring protein tyrosine kinase inhibitor, to inhibit leiomyoma cell proliferation in vitro.
  
  
  METHODS
  Establishment of paired cultures of leiomyoma and normal myometrial samples.
  
  
  METHODS
  University clinical research laboratory.
  
  
  METHODS
  Hysterectomy specimens from premenopausal women affected by uterine leiomyomas.
  
  
  METHODS
  The suppressive effect of TKS050 and genistein on the cells, before and after steroidal hormone treatment, was examined.
  
  
  METHODS
  Cell proliferation, recovery after treatment, cell cycle analysis, and immunochemical analysis of relevant proteins were performed.
  
  
  RESULTS
  TKS050 (2 micromol/L) and genistein (50 micromol/L) completely suppressed leiomyoma cell proliferation, and the cells did not recover after cessation of treatment. TKS050 induced cell cycle arrest and apoptosis in a dose- and time-dependent manner. Cells accumulated in the G(0)/G(1) phase of the cell cycle at the expense of the S and G(2)+M phases. Treatment of cells with TKS050 resulted in a dose-dependent inhibition of EGFR autophosphorylation and of phosphorylated signal transducer and activator of transcription 3 (Stat3). Genistein inhibited the phosphorylated Stat3 but did not affect EGFR autophosphorylation. The inhibitory effects of TKS050 or genistein were unaffected by the presence of physiologic concentrations of estradiol-17beta.
  
  
  CONCLUSIONS
  Leiomyoma cell growth is effectively blocked by TKS050 and genistein. The inhibitory action of newly developed and natural inhibitors derived from diet may be useful as a possible alternative therapy for leiomyomas.
authors.affiliation: Department of Obstetrics and Gynecology, Hadassah University Hospital, Jerusalem, Israel. shush@cc.huji.ac.il <shush@cc.huji.ac.il>
authors.forename: Asher
authors.initials: A
authors.lastname: Shushan
authors.forename: Hannah
authors.initials: H
authors.lastname: Ben-Bassat
authors.forename: Eyal
authors.initials: E
authors.lastname: Mishani
authors.forename: Neri
authors.initials: N
authors.lastname: Laufer
authors.forename: Benjamine Y
authors.initials: BY
authors.lastname: Klein
authors.forename: Nathan
authors.initials: N
authors.lastname: Rojansky
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D019833:Genistein / Q000008:administration & dosage*; D006801:Humans; D007889:Leiomyoma / Q000378:metabolism* / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; C516395:N-(4-((3,4-dichloro-6-fluoro-phenyl)amino)quinazoline-6-yl)-2-chloroacetamide; D011799:Quinazolines; D019833:Genistein; D011505:Protein-Tyrosine Kinases