Inhibition of leiomyoma cell proliferation in vitro by genistein and the protein tyrosine kinase inhibitor TKS050

Fertil Steril. 2007 Jan;87(1):127-35. doi: 10.1016/j.fertnstert.2006.05.056. Epub 2006 Oct 30.

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.

Design: Establishment of paired cultures of leiomyoma and normal myometrial samples.

Setting: University clinical research laboratory.

Patient(s): Hysterectomy specimens from premenopausal women affected by uterine leiomyomas.

Intervention(s): The suppressive effect of TKS050 and genistein on the cells, before and after steroidal hormone treatment, was examined.

Main outcome measure(s): Cell proliferation, recovery after treatment, cell cycle analysis, and immunochemical analysis of relevant proteins were performed.

Result(s): 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.

Conclusion(s): 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Cell Proliferation / drug effects*
  • Dose-Response Relationship, Drug
  • Female
  • Genistein / administration & dosage*
  • Humans
  • Leiomyoma / metabolism*
  • Leiomyoma / pathology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Quinazolines / administration & dosage*
  • Tumor Cells, Cultured
  • Uterine Neoplasms / metabolism*
  • Uterine Neoplasms / pathology*

Substances

  • Antineoplastic Agents
  • N-(4-((3,4-dichloro-6-fluoro-phenyl)amino)quinazoline-6-yl)-2-chloroacetamide
  • Quinazolines
  • Genistein
  • Protein-Tyrosine Kinases